Treatment of conitions and disease

ABSTRACT

A combination for administration to a mammal which combination employs a therapeutically effective amount of a medicinal and/or therapeutic agent to treat a disease or condition and an amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid sufficient to facilitate the agent&#39;s penetration through the tissue (including scar tissue) at the site to be treated, through the cell membranes into the individual cells to be treated.

FIELD OF INVENTION

[0001] The invention relates to, formulations suitable for use to treatconditions and disease, (for example cancer), the use of suchformulations to treat conditions and disease, methods of treatingconditions and disease, and the delivery of medicinal and therapeuticagents for the treatment of disease and conditions.

BACKGROUND OF THE INVENTION

[0002] In an article entitled “Solid cores of tumors keeping out bestdrugs” by Sandra Blakeslee published in the Jul. 8, 1989 edition of theGlobe and Mail, Toronto, Ontario, Ms. Blakeslee submitted that a growingnumber of researchers believe that a basic misunderstanding of thestructure of solid tumors has led researchers into designing cancerdrugs that are doomed to fail in many patients.

[0003] She relates that, Dr. Herberman, Director of the PittsburghCancer Center, said that for decades, cancer researchers have simplydeveloped drugs, put them in the bloodstream and assumed they would becarried to the tumor giving almost no consideration to how uniformly thedrug is distributed once it reaches the tumor.

[0004] Her article also provided that according to Dr. Judah Folkman, aleading researcher on blood growth factors at the Harvard MedicalSchool, for a long time, physicians have been taught that tumors outgrowtheir blood supply. According to the article that statement is not true.Tumors compress their blood supply. This compression makes it harder toadminister drugs.

[0005] The article provides further that most people think a tumor isnothing but a collection of cancer cells. According to Dr. Jain, anotherresearcher, in reality the tumor is only 50 per cent cells. The otherhalf is blood vessels and interstitial space. Interstitial space in atumor, he said, can be likened to the space between marbles packed in abox.

[0006] The article further provides that no matter how biological agentsare mixed and administered, they must cross a blood-vessel wall and thencross the interstitium to reach their targets, cancer cells. The articlecontinues that every tumor is different and there are different regionswithin each. Moreover, tumors change daily as they grow and rearrangeparts. Most blood vessels inside tumors are highly disorganized as theytake tortuous turns and grow peculiar attachments to nearby vessels.

[0007] In general, Dr. Jain said, as a tumor grows, its outer regionrecruits new blood vessels from surrounding normal tissue. It also formsseveral abnormal blood vessels of its own. As the tumor grows in aconfined space, many of the twisted blood vessels near its center arecrushed. In turn, the tumor cells near them appear to die, although theygrow into active cancer if transplanted in other animals. High pressuresbuild up in these necrotic regions. Both blood vessels and liquid plasmain the interstitial spaces are squeezed. The pressure, therefore,prevents blood-borne molecules, including oxygen, from entering thecentral tumor areas.

[0008] Pressure is not uniform in normal tissue, Dr. Jain said, so alarge molecule such as an antibody would reach its target throughconvection induced by pressure differences. But in the center of atumor, pressure is uniformly high, blocking convection.

[0009] Molecules also migrate by diffusion Dr. Jain said, which issimilar to the way a drop of ink spreads in water.

[0010] But he indicated that he measured antibody diffusion in tumorsand found that it can take days, weeks or months for such largemolecules to reach uniform concentration by diffusion in tumors. Bythen, it may be too late for treatments to do any good.

[0011] Finally, the fluid that builds up in the interstitium slowlyleaks out of the tumor, he said, washing away molecules trying to reachits center.

[0012] In our Canadian Patent Application Serial Number 568,512 wedisclose a new formulation suitable for use for treating cancer (for usein conjunction with at least thermotherapy (hyperthermia) and ifdesired, other modalities (such as chemotherapy or radiation)), theformulation comprising (for example in a pharmaceutically acceptablecarrier):

[0013] (a) a glucose inhibiting (non-toxic) amount of an agent thatblocks the glucose transport protein (active transport molecule in themembrane) of a cell from transporting glucose into the cell, and

[0014] (b) an effective (non-toxic) amount of an agent which (i)enhances penetration and transport of agent (a) through the tissuesurrounding the various cellular elements, generally known as scartissue or fibrous reaction around the cancerous tumor, and (ii) altersthe penetration characteristics of the tissue surrounding the tumor topermit agent (a) to be transported to the center of the tumor.

[0015] We also disclosed a combination and formulation suitable for usefor treating cancer, the combination comprising:

[0016] (a) a glucose inhibiting (non-toxic) amount to an agent thatblocks the glucose transport protein (active transport molecule in themembrane) of a cell from transporting glucose into the cell, and

[0017] (b) an effective (non-toxic) amount of an agent which (i)enhances penetration and transport of agent (a) through the tissuesurrounding the various cellular elements, generally known as scartissue or fibrous reaction around the cancerous tumor, and (ii) altersthe penetration characteristics of the tissue surrounding the tumor topermit agent (a) to be transported to the center of the tumor.

[0018] After the introduction of the formulation or combinationcomprising agents (a) and (b) to the patient which have the effect ofmetabolically compromising the cancer cells of the tumor, the tumor andthe cancer cells making up the tumor are stressed by at leastthermotherapy (hyperthermia) In this regard, when agent (a) istransported into the tumor cells and the tumor cells are stressed, thereis an inadequate amount of glucose available to the tumor cells for themto continue to function metabolically. Thus the tumor cell is impairedin its energy supply and dies. We also disclosed in the application amethod for the treatment of cancer which method comprises administering(for example in a pharmaceutically acceptable carrier):

[0019] (a) a glucose inhibiting (non-toxic) amount of an agent thatblocks the glucose transport protein (active transport molecule in themembrane) of a cell from transporting glucose into the cell, and

[0020] (b) an effective (non-toxic) amount of an agent which (i)enhances penetration and transporting of agent (a) through the tissuesurrounding the various cellular elements, generally known as scartissue or fibrous reaction around the cancerous tumor, and (ii) altersthe penetration characteristics of the tissue surrounding the tumor topermit agent (a) to be transported to the center of the tumor, andsubjecting the cancer cells to hyperthermia (thermotherapy) therapy. Insome instances other modalities (for example chemotherapy and/orradiation therapy) may also be employed.

[0021] The glucose inhibiting (non-toxic) amount of the agent thatblocks the glucose transport protein of a cell from transporting glucoseinto the cell (in cancer cells there appear to be more than in normalcells) may comprise:

[0022] or their analogues including phlorizin glucuronide;4-deoxy-phloretin-2-D-glucoside and the like.

[0023] The effective (non-toxic) amount of the agent which

[0024] (i) enhances penetration and transport of agent (a) through thetissue surrounding the various cellular elements generally known as scartissue or fibrous reaction around the cancerous tumor, and

[0025] (ii) alters the penetration characteristics of the tissuesurrounding the tumor to permit agent (a) to be transported to thecenter of the tumor may comprise dimethyl sulfoxide (DMSO),methylsulfonylmethane (MSM) (also called methylsulfone methane) or othercarrier transport-type molecules having the characteristics which

[0026] (i) enhances penetration and transport of agent (a) through thetissue surrounding the various cellular elements, generally known asscar tissue or fibrous reaction around the cancerous tumor, and

[0027] (ii) alters the penetration characteristics of the tissuesurrounding the tumor to permit agent (a) to be transported to thecenter of the tumor.

[0028] In the publication Ontario Medicine, Volume 8, No. 16 dated Aug.21, 1989 the article “Toxic drug tamed but still potent” describes howan experimental liposomal drug delivery system, is used to encapsulate ahighly toxic but highly effective anti-fungal agent, demonstrating thatnoxious drugs can be transformed into non-toxic agents withoutcompromising clinical efficacy.

[0029] The article concluded as follows:

[0030] “It was initially hoped that liposomes would offer considerablepotential as a drug delivery system for almost all pharmaceuticalagents. However, research into the drug delivery system over the pasttwo decades has shown that the artificial, cell-sized spheres formspontaneously with only a small subset of drugs available today thuslimiting their use.”

[0031] Hoffer in a study explored the effects of ascorbic acid (VitaminC) in respect of the health of patients. In the article he discussed theeffects of Vitamin C with respect to cancer treatment. He also discussedthe findings of Cameron and Pauling of the use of ascorbic acid in 10gram doses to treat cancer patients and which administration of theascorbic acid increased the survival of terminally ill cancer patients.He also discussed the safety of the use of ascorbic acid and the safteyin very high doses. He stated at page 11 of his study that the ascorbicacid was water soluble, was bulky but had no LD-50. Hoffer states that

[0032] “When the vitamin cannot be absorbed completely from thegastrointestinal system, it will remain water in the bowel leading todiarrhea, which is watery but not dangerous unless it causesdehydration; it quicky forces patients to decrease the doses. It has andis being used by millions of people in these doses. Patients I haveknown have taken 30 grams per day for 30 years. It is safer than commontable salt, gram for gram. It does not cause kidney stones, does notcause pernicious anemia, does not make women infertile, does not causecancer.”

[0033] It is therefore an object of this invention to provideformulations suitable for use to treat disease and conditions, the useof such formulations to treat disease and conditions, methods oftreating disease and conditions and the delivery of medicinal andtherapeutic agents for the treatment of disease (for example, cancer)and conditions.

[0034] Further and other objects of the invention will be realized bythose skilled in the art from the following disclosure and in whichApplicants refer to literature uncovered after the date of theirinvention.

[0035] Hyaluronic acid is a naturally occurring glycosaminoglucan. Itsmolecular weight may vary from 50,000 dalton upwards, and it formshighly viscous solutions. As regards the actual molecular weight ofhyaluronic acid in natural biological contexts, this is still a matterof much uncertainty: When the molecular weight of hyaluronic acid is tobe determined, different values are obtained depending on the assaymethod employed, and on the source, the isolation method etc. The acidoccurs in animal tissue, e.g. spinal fluid, ocular fluid, synovialfluid, cockscombs, skin, and also in some streptococci. Various gradesof hyaluronic acid have been obtained. A preparation with an allegedlyhigh degree of purity and alleged to be entirely free from side effects,is a non-inflammatory form described in U.S. Pat. No. 4,141,973; thispreparation is said to have a molecular weight exceeding 750,000 dalton,preferably exceeding 1,200,000 dalton and is suggested for therapeuticuse in various articular conditions.

[0036] U.S. Pat. No. 4,801,619 relates to hyaluronic acid administeredintra-articularly having a molecular weight of about 3×10⁶ dalton ormore, which is prone to decrease the proteoglycan content of synovialfluid to almost normal levels. According to this patent, this indicatesa positive effect on the proteoglycan metabolism of a joint. Accordingto the Patent this is applicable both to inflammatory conditions and todegeneration caused by treatment with symptomatics, such ascorticosteroid preparations. It is thus clear that a sufficiently highmolecular weight of the hyaluronic acid is alleged to counteract sideeffects that might be caused by corticosteroids or other symptomaticsproducing similar effects. When corticosteroids are applied, the amountof hyaluronic acid in the synovial cavity will according to the Patentincrease substantially and according to the inventors their hyaluronicacid preparations have a very positive effect on such clinical symptomsas pain, swelling and lameness.

[0037] The patent states that the objectives of the invention areattained by intra-articular administration of an effective amount ofhyaluronic acid with a mean molecular weight exceeding 3×10⁶ dalton,preferably exceeding 4×10⁶ dalton; usually the molecular weight will notexceed 7×10⁶ dalton. The dosage of hyaluronic acid administered isstated to be preferably within the range of 5 mg-80 mg. The amount ofsolution given at each administration is generally less than 60 ml, e.g.less that 20 ml, of an aqueous solution of the acid or its salt. It isconvenient to administer the acid dissolved in water (<2% w/w, bufferedto physiological pH), for instance in the form of a water-soluble sodiumsalt. The exact amount will depend on the particular joint to betreated.

[0038] The Merck Index Specifies that Hyaluronic Acid has a MolecularWeight within the range pf 50,000 to 8×10⁶ depending on source, methodsof preparation and methods of determination. The Merck Publicationteaches hyaluronic acid as a surgical aid (ophthalmological).

[0039] U.S. Pat. No. 4,808,576 purports to teach that hyaluronic acid,an agent well known to reduce the sequelae of trauma in mammalian jointtissue when applied directly to the traumatized tissue, will be carriedto such traumatized tissue by the mammal's natural processes if appliedat a site remote from the traumatized tissue. Thus hyaluronic acid inany therapeutically acceptable form can, according to the Patent, beadministered by the typical remote routes including intravenous,intramuscular, subcutaneous and topical.

[0040] This, the patent alleges, makes the utilization of hyaluronicacid much more convenient and attractive. For instance the treatment ofarthritis in horse. or human joints with hyaluronic acid according tothe patent no longer requires more difficult intra articular injections.

[0041] U.S. Pat. No. 4,725,585 relates to a method of enhancing orregulating the host defence of a mammal, said method comprisingadministering to a mammal a therapeutically effective amount ofhyaluronic acid.

[0042] At column 1 lines 43-46, the patent provides that the inventionwas based on the unexpected discovery that administration of hyaluronicacid to mammals results in a considerable increase in the defence.

[0043] The hyaluronic acid employed in the Patent was Healon (T.M.)provided by Pharmacia AB, Uppsala, Sweden (Pharmacia AB is also entitledto the benefit of U.S. Pat. No. 4,141,973). The patent provides atcolumn 4, line 19 that because a patient's infections had been hard totreat, instead of just hyaluronic acid, being administered to thepatient to increase the patient's defence, the patient was givenhyaluronic acid and an antibiotic. While the patent states that theantibiotic was given in combination with hyaluronic acid, in factbecause the hyaluronic acid was administered subcutaneously and becausethe patient was a heart patient, one skilled in the art would understandthat any antibiotic administered, while possibly administeredsimultaneously was definitely administered separately intravenously(probably) or intramuscularly (less probably) Thus, (most probably) thehyaluronic acid administered according to the teachings of this patentwas administered in order to prevent possible development of infections(increase the host's defence) and not for any other reason.

[0044] U.S. Pat. No. 4,636,524 discloses cross-linked gels of hyaluronicacid, alone and mixed with other hydrophilic polymers and containingvarious substances or covalently bonded low molecular weight substancesand processes for preparing them. These products are alleged to beuseful in numerous applications including cosmetic formulations and asdrug delivery systems.

[0045] The patent further states that as hyaluronic acid is known to bea biologically tolerable polymer in the sense that it does not cause anyimmune or other kind of response when introduced into a human body, thecross-linked hyaluronic acid gels can be used for various medicalapplications. The cross-linked gels modified with other polymers or lowmolecular weight substances it is alleged can be used as drug deliverydevices. For example, the inventors are alleged to have found thatheparin introduced in a cross-linked hyaluronic acid gel retained itsantithrombogenic activity.

[0046] The inventors also allege that they have also found thatcross-linked gels of hyaluronic acid can slow down the release of a lowmolecular weight substance dispersed therein but not covalently attachedto the gel macromolecular matrix.

[0047] U.S. Pat. No. 4,736,024 purports to teach new medicaments fortopical use containing:

[0048] (i) an active pharmacological substance or a mixture ofpharmacological substances, either active or suitable for topicaladministration and

[0049] (ii) a topical vehicle which comprises hyaluronic acid or amolecular fraction of hyaluronic acid or a salt of the same with analkaline metal, an alkaline earth metal, magnesium, aluminium, ammoniumor a pharmacological substance, optionally together with additionalconventional excipients for pharmaceutical preparations for topical use.

[0050] Applicants are also aware of recently published Japanese PatentDocument 61000017 dated 86/01/06 whose English abstract of disclosurestates that the Japanese Patent Document relates to the use ofhyaluronic acid or cross-linked hyaluronic acid or their salts as theactive ingredient for inhibiting carcinoma metastasis.

[0051] According to the purported abstract of the Patent more that 1.0%of hyaluronic acid is dissolved in alkaline aq. soln. and pref. morethan 50% of H₂O sol. org. solvent. eq. alcohol, acetone, dioxane,against total soln. is added. Preferably the pH is 12-14. Thenmultifunctional epoxy cpd. is added and reacted at 10-60 deg. C., pref.at 20-40-deg. C. for 24 hrs. Cross-linking ratio of crosslinkedhyaluronic acid or its salt is regulated by changing mol ratio ofhyaluronic acid or its salt and multifunctional epoxy cpd. Pref.hyaluronic acid used has intrinsic viscosity 0.2-30, m.w. 4000-2000000.The hyaluronic acid is allegedly used in several dosage forms. Clinicaldose for adult is alleged to be normally, as hyaluronic acid orcross-linked hyaluronic acid, 25 mg-5 g/day (p.o.) and 10 mg-2.5 g/ldose (inj). The abstract alleges that the advantage is that thehyaluronic acid has no side effects as other anticancer drugs and has ananalgesic and a tissue restoration effect.

[0052] European Patent Application 0295092 purports to teach a vehicletogether with fragments of hyaluronic acid for delivering of thefragments of hyaluronic acid into the skin to reach the dermal layer ofthe skin to increase the development of blood vessels for stimulatinghair growth or regrowth. The preferred fragments of hyaluronic acid arepolysaccharides containing from 7 to 25 monosaccharide units. The patentprovides it is apparent that the larger the fragments of hyaluronicacid, the greater the difficulty there is in delivering the fragments tothe dermal layer of the skin, unless there is also present in thecomposition a means for enhancing the activity of said fragments.

[0053] The combination may thus include a means for enhancing theactivity of the fragments of hyaluronic acid especially to improve theirpenetration through the skin following topical application. Someactivity enhancers, it is alleged, also function as vehicles for thefragments of the hyaluronic acid.

[0054] Some activity enhancers are also alleged to possess the abilityto stimulate or increase hair growth. Minoxidil is asserted among othersto be such an activity enhancer.

[0055] Thus both the fragments of hyaluronic acid and minoxidil arealleged to stimulate hair growth both delivered by a vehicle.

[0056] European Patent Application 0179442 asserts that where freeradicals are formed in considerable quantities, hyaluronic acid isbroken down or degraded before the hyaluronic acid has given the desiredeffect.

[0057] Canadian Letters Patent 1,240,929 teaches the combination ofchondroitin sulfate compound and a hyaluronate to protect both human andanimal cell layers and tissue subject to exposure to trauma.

[0058] European Patent Application 0208623 purports to teach hyaluronicacid as une augmentation de l'activite de certaines proteases. It alsopurports to teach the use of hyaluronic acid for treating connectivetissue diseases including malignant tumors and cardiovascular disorders.

[0059] European Patent Application 270317 purports to teach thecombination of an antiviral agent lacking inhibitory action and acompound [for example, hyaluronic acid] possessing cell fusioninhibitory activity and/or virus-adsorption inhibitory activity fortreating disease carried by a virus.

[0060] U.S. Pat. No. 4,840,941 purports to teach the use of an effectiveamount of hyaluronic acid as the active agent for the treatment ofretroviruses in association with a pharmaceutically acceptable carrier,diluent or excipient.

[0061] U.S. Pat. No. 4,851,521 and European Patent Application 0265116both describe hyaluronic acid fractions, the making thereof andcross-linked esters of hyaluronic. U.S. Pat. No. 4,851,521 describesesters of hyaluronic acid incorporated into pharmaceutical preparationsas the active ingredient and as vehicles for ophthamological medicinesfor topical use (See column 11, lines 35 to 42; and column 12, lines 62to column 13, line 3) and in suppositories for a systemic effect due tothe effect of transcutaneous absorption, such as in suppositories.

[0062] The patent provides at column 13, lines 5 to 31: “The vehiclingaction of the hyaluronic esters also applies to associated medicamentsof the type mentioned above in which the active substance acts not onlytopically or by nasal or rectal absorption, for example by nasal spraysor preparations for inhalation for the oral cavity or the pharynx, butalso by oral or parenteral route, for example by intramuscular,subcutaneaous or intravenous route, as it favors absorption of the druginto the application site. The new medicaments can therefore be applied,apart from in the fields already mentioned, in practically all sectorsof medicine, such as internal medicine, for example in pathologies ofthe cardiovascular system, in infections of the respiratory system, thedigestive system, the renal system, in diseases of an endocrinologicalnature, in oncology, in psychiatry etc., and may also be classifiedtherefore from the point of view of their specific action, being perhapsanesthetics, analgesics, anti inflammatories, wound healers,antimicrobics, adrenergic agonsits and antagonists, cytostatics,antirheumatics, antihypertensives, diuretics, sexual hormones,immunostimulants and immunosuppressants, for example, one of the drugshaving the activity already described for the therapeutically activealcohols to be used as esterifying component according to the presentinvention, or for the therapeutically active bases used for thesalification of the free carboxylic groups.”

[0063] Furosemide inhibits sodium reabsorption in the ascending limb ofHenle's Loop and in both proximal and distal tubules. The action of thedrug is independent of any inhibitory affect on carbonic anhydrase oraldosterone. Furosemide is known to promote diuresis in cases which havepreviously proved resistant to other diuretics. It has—no significantpharmalogical effects other than on renal function. In the human it isabsorbed from the gastrointestinal tract. Following intravenousadministration a diuresis generally occurs within 30 minutes and theduration of action is about 2 hours.

[0064] Under a variety of circumstances, the patient can becomerelatively resistant to the effects of Lasix. This can be so for avariety of reasons but is certainly seen in those situations where thereis a major amount of peripheral edema or “third spacing” of fluid whichmay be true in malnutrition and/or advanced carcinomas. In the latterinstances, there is a markedly decreased level of albumin and in allprobability, increased permeability and transudation of fluid out of thevascular system. Hence, these patients can become relatively resistantto any of the diuretics including high doses: of Lasix administeredintravenously.

[0065] There have been extensive studies to determine the defect inimmune function that allows a tumor cell to develop. It was postulatedinitially by Jerne, and subsequently by Burnett that the immune system'smajor role was that of immunological surveillance to destroy abnormalcells. The concept of surveillance, while somewhat simplistic, remainsan accepted concept for the elaborate mechanism of immune recognitionand-function that is present in the higher species—mammals.

[0066] It has then been postulated that tumors develop because of localor generalized immune suppression. However, as pointed out by Moller, ifgeneral immune suppression occurs, it is only certain types ofneoplastic disorders that develop, mainly those of the lympho-reticularsystem. This observation is correct and represents a major challenge tothe immune surveillance theory unless a specific reason can be shown asto why the individual cancer cell can develop plus individually evadethe immune system.

[0067] It was demonstrated experimentally in 1974 that defects ofmacrophage function may exist in neoplastic disease.

[0068] The initial experiments found suppressor cells to be part of theimmune system; these were either of the T-cell type of the macrophagecell system. There was presence demonstrated in neoplasia, chronicbacterial infection, recovery from massive injury and chronic fungalinfection.

[0069] There has been repeated demonstration in experimental animals,that the macrophage cell function is altered in neoplastic disease. Themacrophages in the animal's systems appeared “blocked” in theirfunction. Generally when removed from the in vivo situation, washed insaline and cultured, they could perform normally. This block has beenshown to be related to the excessive production of prostaglandin byneoplastic tissue or by the macrophage itself.

[0070] In the basic research efforts in the latter '70s and the early80's, there existed considerable confusion as to what role immunotherapyshould take in cancer. Activation or “hyping” of macrophages was thoughtto be important. However, in an examination by Romans and Falk ofperitoneal macrophages obtained from patients with neoplastic disease,there was definite evidence that these macrophages were alreadyactivated yet were co-existing. with cancer cells and not causing theirdestruction.

[0071] In the early part of this year it has been shown by severalindependent investigators that the malfunction of macrophages or theputitive block is due to excessive prostaglandin and that this can bealtered in tissue culture by corticosteroids, ASA, and the non-steroidalanti-inflammatory drugs, i.e. indomethacin, and naproxen (Naprosy™).Again, in animal tumors it was repeatedly demonstrated that thesesubstances could alter the response to neoplastic cells and that variouscombinations of these substances employed with immune enhancing agentscould produce very credible success in eliminating experimental tumors.Lala and co-workers combined Indomethacin therapy with Interleukin 2 andshowed that this could effect a cure with experiment neoplasm.

[0072] There were continued problems with the use of any of these agentsin the actual human in vivo experience. All—of the non-steroidalanti-inflammatory agents (NSAID) produced major toxicity in terms ofgastro-intestinal, neurological, and other areas. Thus, the basis of thepresent approach is that under general circumstances the use of theseagents in human disease, in sufficient amounts, the drug will penetrateto any pathological tissue to alter therapeutically local prostaglandinproduction. While intravenous preparations exist of Indomethacin and nowof other agents, the data is overwhelming, as is our own experience,that using these drugs alone produces prohibitive side effects in humansubjects. Therefore only insufficient amounts can be brought into thebody to effect more than occasional responses in neoplasm.

[0073] However the majority of the evidence is present to indicate andtherefore it can be postulated that the basis for neoplastic developmentand how the initial cell “sneaks by” the immune surveillance mechanismrelates to its production of prostaglandin. One need postulate only onemutation to alter the amount of prostaglandin synthesis produced bycells when they become “malignant” to establish a mechanism of blockingout the initial cell in any immune reaction, i.e. the macrophage. Ittherefore became essential to develop a combination of NSAIDS forclinical use to produce a major improvement in response in neoplasticdisease and other, conditions where excessive prostaglandin synthesisrepresents the basis of the pathogenesis of this disease state, i.e.arthritis, and various others of the so-called connective tissueinflammatory disorders and/or auto-aggressive diseases.

[0074] See also:

[0075] 1. Modulation of Immunity in Cancer Patients by ProstaglandinAntagonists, Immunity to Cancer II, Alan R. Liss, Inc.; and

[0076] 2. Goodwin, J. S. (1981) Prostaglandin E and Cancer GrowthPotential for Immunotherapy with Prostaglandin Synthesis Inhibitors,Augmentive Agents in Cancer Therapy, Raven Press, New York.

[0077] U.S. Pat. No. 4,711,780 teaches a pharmaceutical compositioncomprising Vitamin C, a zinc salt, a sulfur amino acid for treatingsurface epithelium for epithelium regeneration. Hyaluronic acid may beadded for applications in the reproductive tract.

[0078] Japanese Patent Publication 63/045223 relates to the treatment ofdisease caused by retroviruses. Hyaluronic acid is taught for preventionor therapy of leukemia or AIDS by suppressing replication of the virus.

[0079] An article entitled “Inactivation of Herpes Simplex Viruses byNonionic Surfactants” by one of the inventors herein (Dr. SamuelAsculai) among others [published in Antimicrobial Agents andChemotherapy, April 1978, pp.686-690] disclosed nonionic surface-activeagents, for example nonoxynol-9 found in Delfe™, “possessing ether oramide linkages between the hydrophilic and hydrophobic portions of themolecule rapidly inactivated the infectivity of herpes simplex viruses.The activity stemmed from the ability of nonionic surfactants todissolve lipid-containing membranes. This was confirmed by observingsurfactant destruction of mammalian cell plasma membranes and herpessimplex virus envelopes. Proprietary vaginal contraceptive formulationscontaining nonionic surfactants also inactivated herpes simplex virusinfectivity. This observation suggests that nonionic surfactants inappropriate formulation could effectively prevent herpes simplex virustransmission.”

SUMMARY OF THE INVENTION

[0080] Applicants have now discovered that combinations and formulations(for example an injectable formulation) can be provided foradministration to a mammal for the treatment of a disease or condition,which combinations or formulations employ or incorporate as the case maybe a therapeutically effective non-toxic amount of a medicinal and/ortherapeutic agent to treat the disease or condition (for example a freeradical scavenger (for example ascorbic acid (Vitamin C)), Vitamin C(for the treatment of mononucleosis), an anti-cancer agent,chemotherapeutic agent, anti-viral agents for example a nonionicsurfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found inDelfe™ contraceptive cream, and anionic surfactants (e.g. cetylpyridinium chloride) and cationic surfactants (e.g. benzalkoniumchloride), non-steroidal anti-inflammatory drugs (NSAID) for exampleindomethacin, naproxen and (+/−) tromethamine salt of ketorolac (soldunder the trademark Toradol™) and steroidal anti-inflammatory drugs,anti-fungal agent, detoxifying agents (for example for administrationrectally in an enema), analgesic, bronchodilator, anti-bacterial agent,antibiotics, drugs for the treatment of vascular ischemia (for examplediabetes and Berger's disease), anti-body monoclonal agent, minoxidilfor topical application for hair growth, diuretics (for examplefurosemide (sold under the trademark Lasix™)), immunosuppressants (forexample cyclosporins), lymphokynes (such as interleukin-2 and the like),alpha-and-β-interferon and the like) administered with, or carried in,an amount of hyaluronic acid and/or salts thereof (for example thesodium salt) and/or homologues, analogues, derivatives, complexes,esters, fragments, and/or sub units of hyaluronic acid (preferabLyhyaluronic acid and salts thereof) sufficient to facilitate the agent'spenetration through the tissue (including scar tissue), at the site tobe treated through the cell membranes into the individual cells to betreated. When such combinations and formulations are administered topatients suffering from the disease or condition, the disease orcondition is unexpectedly improved

[0081] The formulation can be administered among other methods,intravenously, intra arterially, intraperitoneally, int-rapleurally,transdermally, on the skin (topically), rectally, orally or by directinjection (for example into a tumor, into an abscess or similar diseasefocus) or put on a patch to be secured to the skin of the patient. Thehyaluronic acid and/or salts thereof and the agent can be administeredseparately but are administered in sufficient amounts and in animmediate time sequence or interval (preferably concurrently and morepreferably simultaneously), preferably at the identical site (e.g. onegiven intravenously and the other “piggy backed”), to treat the diseaseor condition.

[0082] Thus according to an aspect of the invention, a combination isprovided suitable for use to treat a condition, or disease, thecombination comprising therapeutically effective non toxic amounts of

[0083] (a) a medicinal and/or therapeutic agent to treat a disease orcondition (for example a free radical scavenger (for example ascorbicacid (Vitamin C)), Vitamin C (for the treatment of mononucleosis), ananti-cancer agent, chemotherapeutic agent, anti-viral agents for examplea nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxyethanol] found in Delfe™ contraceptive cream, and anionic surfactants(e.g. cetyl pyridinium chloride) and cationic surfactants (e.g.benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID)for example indomethacin, naproxen and (+/−) tromethamine salt ofketorolac (sold under the trademark Toradol™) and steroidalanti-inflammatory drugs for example *), anti-fungal agent, detoxifyingagents (for example for administration rectally in an enema), analgesic,bronchodilator, anti-bacterial agent, antibiotics, drugs for thetreatment of vascular ischemia (for example diabetes and Berger'sdisease), anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics (for example furosemide (sold under thetrademark Lasix™)) immunosuppressants (for example cyclosporins),lymphokynes (such as interleukin-2 and the like), alpha-and-β-interferonand the like) and

[0084] (b) a sufficient amount of hyaluronic acid and/or salts thereof(for example sodium salt) and/or homologues, analogues, derivatives,complexes, esters, fragments, and/or subunits of hyaluronic acid,preferably hyaluronic acid and salts thereof, sufficient to facilitatethe agent's penetration through the tissue (including scar tissue) atthe site to be treated through the cell membranes into the individualcells to be treated.

[0085] The combination can be administered separately, or as a mixtureor solution. If administered separately the components are preferablyadministered simultaneously and at the identical site.

[0086] According to another aspect of the invention, a formulation isprovided suitable for use to treat a condition or disease, theformulation comprising a therapeutically effective non-toxic amount of amedicinal and/or therapeutic agent to treat a disease or condition (forexample a free radical scavenger (for example a free radical scavenger(for example ascorbic acid (Vitamin C)), Vitamin C (for the treatment ofmononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viralagents for example a nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxypolyethoxy ethanol] found in Delfen™ contraceptive cream, and anionicsurfactants (e.g. cetyl pyridinium chloride) and cationic surfactants(e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs(NSAID) for example indomethacin, naproxen and (+/−) tromethamine saltof ketorolac (sold under the trademark Toradol™) and steroidalanti-inflammatory drugs, anti-fungal agent, detoxifying agents (forexample for administration rectally in an enema), analgesic,bronchodilator, anti-bacterial agent, antibiotics, drugs for thetreatment of vascular ischemia (for example diabetes and Berger'sdisease), anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics (for example furosemide (sold under thetrademark Lasix™)), immunosuppressants (for example cyclosporins),lymphmokynes (such as interleukin-2 and the like),alpha-and-β-interferon and the like), in an amount of hyaluronic acidand/or salts thereof (for example the sodium salt) and/orhomologues,analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid, preferably hyaluronic acid and salts thereof,sufficient to facilitate the agent at the site to be treated, topenetrate through the tissue (including scar tissue) through cellmembranes into the individual cells to be treated.

[0087] According to another aspect of the invention a method of treatinga condition or a disease in a mammal is provided comprisingadministering to the mammal, a combination of a therapeuticallyeffective non-toxic amount of

[0088] (a) a medicinal and/or therapeutic agent to treat a disease orcondition (for example a free radical scavenger (for example ascorbicacid (Vitamin C)), Vitamin C (for the treatment of mononucleosis), ananti-cancer agent, chemotherapeutic agent, anti-viral agents for examplea nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxyethanol] found in Delfen™ contraceptive cream, and anionic surfactants(e.g. cetyl pyridinium chloride) and cationic surfactants (e.g.benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID)for example indomethacin, naproxen and (+/−) tromethamine salt ofketorolac (sold under the trademark Toradol™) and steroidalanti-inflammatory drugs, anti-fungal agent, detoxifying agents (forexample for administration rectally in an enema), analgesic,bronchodilator, anti-bacterial agent, antibiotics, drugs for thetreatment of vascular ischemia (for example diabetes and Berger'sdisease), anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics (for example furosemide (sold under thetrademark Lasix™)), immunosuppressants (for example cyclosporins),lymphokynes (such as interleukin-2 and the like), alpha-and-β-interferonand the like) and

[0089] (b) a sufficient amount of hyaluronic acid and/or salts thereof(for example sodium salt) and/or homologues, analogues, derivatives,complexes, esters, fragments, and/or sub units of hyaluronic acid,preferably hyaluronic acid and salts thereof sufficient to facilitatethe agent at the site to be treated to penetrate through the tissue(including scar tissue), through the cell membranes into the individualcells to be treated.

[0090] Preferably (a) and (b) are administered simultaneously at theidentical site, for example, one intravenously and the other “piggybacked”.

[0091] According to another aspect of the invention a method of treatingdisease or a condition is provided comprising administering to a mammala therapeutically effective non toxic amount of a formulation comprisinga therapeutically effective amount of a medicinal and/or therapeuticagent to treat a disease or condition (for example a vitamin (forexample a free radical scavenger (for example ascorbic acid (VitaminC)), Vitamin C (for the treatment of mononucleosis), an anti-canceragent, chemotherapeutic agent, anti-viral agents for example a nonionicsurfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found inDelfen™ contraceptive cream, and anionic surfactants (e.g. cetylpyridinium chloride) and cationic surfactants (e.g. benzalkoniumchloride), non-steroidal anti-inflammatory drugs (NSAID) for exampleindomethacin, naproxen and (+/−) tromethamine salt of ketorolac (soldunder the trademark Toradol™) and steroidal anti-inflammatory drugs,anti-fungal agent, detoxifying agents (for example for administrationrectally in an enema), analgesic, bronchodilator, anti-bacterial agent,antibiotics, drugs for the treatment of vascular ischemia (for examplediabetes and Berger's disease), anti-body monoclonal agent, minoxidilfor topical application for hair growth, diuretics (for examplefurosemide (sold under the trademark Lasix™)), immunosuppressants (forexample cyclosporins), lymphokynes (such as interleukin-2 and the like),alpha-and-β-interferon and the like) in an amount of hyaluronic acidand/or salts thereof (for example the sodium salt) and/or homologues,analogues, derivatives, complexes, esters, fragments and/or sub units ofhyaluronic acid, preferably hyaluronic acid and salts thereof,sufficient to facilitate the agent at the site to be treated topenetrate through the tissue (including scar tissue) through cellmembranes into the individual cells to be treated.

[0092] According to another aspect of the invention, delivery of atherapeutically effective amount of a medicinal and/or therapeutic agentto treat a disease or condition in a mammal is provided, the deliverycomprising administering a therapeutically effective non toxic amount ofa medicinal and/or therapeutic agent (for example a free radicalscavenger (for example ascorbic acid (Vitamin C)), Vitamin C (for thetreatment of mononucleosis), an anti-cancer agent, chemotherapeuticagent, anti-viral agents for example a nonionic surfactant, e.g.nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in Delfen™contraceptive cream, and anionic surfactants (e.g. cetyl pyridiniumchloride) and cationic surfactants (e.g. benzalkonium chloride),non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin,naproxen and (+/−) tromethamine salt of ketorolac (sold under thetrademark Toradol™) and steroidal anti-inflammatory drugs, anti-fungalagent, detoxifying agents (for example for administration rectally in anenema), analgesic, bronchodilator, anti-bacterial agent, antibiotics,drugs for the treatment of vascular ischemia (for example diabetes andBerger's disease), anti-body monoclonal agent, minoxidil for topicalapplication for hair growth, diuretics (for example furosemide (soldunder the trademark Lasix™)), immunosuppressants (for examplecyclosporins), lymphokynes (such as interleukin-2 and the like),alpha-and-β-interferon and the like) with a sufficient amount ofhyaluronic acid and/or salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments, and sub units of hyaluronicacid, preferably hyaluronic acid and salts thereof, sufficient totransport or facilitate the transport of, the agent to the site to betreated through the cell membranes into the individual cells to betreated.

[0093] Thus according to another aspect of the invention, use of acombination or formulation is provided to treat a disease or condition,the combination and formulation comprising a therapeutically effectivenon-toxic amount of a medicinal and/or therapeutic agent to treat adisease or condition (for example a vitamin (for example a free radicalscavenger (for example ascorbic acid (Vitamin C)), Vitamin C (for thetreatment of mononucleosis), an anti-cancer agent, chemotherapeuticagent, anti-viral agents for example a nonionic surfactant, e.g.nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in Delfen™contraceptive cream, and anionic surfactants (e.g. cetyl pyridiniumchloride) and cationic surfactants (e.g. benzalkonium chloride),non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin,naproxen and (+/−) tromethamine salt of ketorolac (sold under thetrademark Toradol™) and steroidal anti-inflammatory drugs, anti-fungalagent, detoxifying agents (for example for administration rectally in anenema), analgesic, bronchodilator, anti-bacterial agent, antibiotics,drugs for the treatment of vascular ischemia (for example diabetes andBerger's disease), anti-body monoclonal agent, minoxidil for topicalapplication for hair growth, diuretics (for example furosemide (soldunder the trademark Lasix™)), immunosuppressants (for examplecyclosporins), lymphokynes (such as interleukin-2 and the like),alpha-and-β-interferon and the like) and a sufficient amount ofhyaluronic acid and/or saltsv thereof (for example sodium salt) and/orhomologues, analogues, derivatives, complexes, esters, fragments, and/orsub units of hyaluronic acid, preferably hyaluronic acid and saltsthereof to facilitate agent transported to the site to be treated, topenetrate through the cell membranes into the individual cells to betreated.

[0094] Applicants postulate that the hyaluronic acid and/or saltsthereof and/or the homologues, analogues, derivatives, complexes,esters, fragments, and/or sub units of hyaluronic acid facilitate thetransport of the agent to the site to be treated and to penetrate thetissue (including scar tissue) through all membranes in the individualcells to be treated.

[0095] By way of example and to illustrate the facilitation of thedelivery -or transport of a chemical to a site in a mammal, when ethylalcohol is injected directly into a tumor, and sonographic (ultrasound)assessment is made, it is not dispersed throughout the tumor. When theethyl alcohol to be administered into a tumor is carried by hyaluronicacid and/or salts thereof, sonographic assessment of the tumor,demonstrates the dispersion of the ethyl alcohol throughout the tumor.

[0096] While Applicants postulate that the hyaluronic acid facilitatesthe transport and delivery, Applicants' invention may be used asdescribed irrespective of the actual method of operation of thehyaluronic acid and/or salts thereof and/or the homologues, analogues,derivatives, complexes, esters, fragments and sub units of hyaluronicacid.

[0097] The combination of hyaluronic acid and salts thereof and otherforms with different chemicals and drugs (Vitamin C, anti-cancer drugs,etc.) alters their distribution and performance in the human body andproduces an unusual targeting for underperfused tissue and/orpathological tissue. In this regard the use of ascorbic acid (Vitamin C)as a free radical scavenger (50 gm daily—1000 times the daily dose intherapeutic purposes as a Vitamin) administered intravenously with300-500 mg of hyaluronic acid (sodium hyaluronate) immediately relievesbone pain and muscle pain and reduces inflammation in cancer patients.The hyaluronic acid enhances the anti-neoplastic activity and effect ofthe ascorbic acid. It is thought that this enhanced activity eliminatesthe free radicals by acting as a free radical scavenger. In any eventthe patients feel better. This is also demonstrated with furosemide andhyaluronic acid where the activity of furosemide is enhanced onlyminimally when administered with hyaluronic acid to a “normal” subjectbut the activity is enhanced significantly when administered to apatient whose kidney is underperfused or malfunctioning due toinsufficient intra-vascular volume.

[0098] A similar situation occurs with the NSAIDS. As a major amount ofsoluble indbmethacin is required, the chemical product was solubilizedusing n-methyl glucamine at a dilution of 5 mg/ml of n-methyl glucamine(NMG). This substance is then passed through a 22 micron Milipore filterto produce sterility. This material is non-toxic at 16 fold thetherapeutic dose in animals and for this reason was consideredappropriate to be used in human conditions. Thus, Indocid™ solubilizedin NMG is administered to human patients either into the tumorintraperitoneally, intrapleurally, or intravascularly at a varying doseup to 10 mg/kg where each dose of indomethacin is combined with 200-1000mg of hyaluronic acid (for example “LifeCore™” hyaluronic acid [sodiumhyaluronate]) diluted in the original solution of indomethacin and NMGwith for example the “LifeCore™” hyaluronic acid. This produces anappropriate mixture and can be administered safely by any of the routes.[Similar clinical studies have been done with hyaluronic acid preparedby other methods, i.e. extraction. The extracted material issatisfactory to use for intratumor, intraperitoneal or intrapleural usewith this substance.]

[0099] Thus and according to another aspect of the invention when anNSAID for example indomethacin (dissolved in n-methyl glucamine) orother NSAID is administered with greater than 200 mg hyaluronic acid for1-12 mg/kg body weight of the NSAID (in one instance indomethacin andNMG), no major toxic side effects occur such as gastro-intestinaldistress, neurological abnormalities, depression, etc., even at elevatedamounts of indomethacin (if necessary). If the amount of hyaluronic acidis decreased below that amount, the usual side effects may begin toreoccur. In addition, the responses that have been observed are superiorwhen the NSAID (for example Indocid™) is combined with hyaluronic aciddemonstrating clearly that the combination is now “targeting” to thepathological tissue even when administered by the systemic intravenousroute. Thus, it has been observed that patients with neoplastic diseaseswhen receiving in addition to other chemicals (for example ascorbic acid[Vitamin C], phloretin and anti-cancer drugs), 50-200 mgNSAID—hyaluronic acid (sodium hyaluronate) (for example indomethacin andhyaluronic acid) experience dramatic relief of pain immediately. This isfollowed within a short period of time by a resolution and resorbtion ofneoplastic lesions with an improvement of pulmonary, and liver functionif there is tumor present in these organs. Thus the dead tumor materialand the debris and tumor toxins appear to be better eliminated by thebody through the action of the macrophages whose activity is enhanced bythe addition of the NSAID (or a steroidal anti-inflammatory drug)administered with hyaluronic acid (or salt or other form thereof). ThusApplicants believe that the addition of the NSAID for example withhyaluronic acid (sodium hyaluronate) deblocks the macrophages bypreventing enzymatic production of prostaglandin synthetase which blocksmacrophage functioning. Thus the hyaluronic acid (and salt and otherforms) not only enhance the activity of the NSAID but also reduce anyside effects and toxicity that is associated with the use of theprostaglandin synthesis inhibitors.

[0100] Examples of agents suitable for use as chemotherapeutic agentsare novantrone (Mitoxantrone), Methotrexate, 5-FU (5-Fluouracil),carboplatinum, methyl CCNU administered orally and Mitomycin C.

[0101] In one instance methotrexate has been administered withhyaluronic acid over an area of tumor tissue, (e.g. the chest wall) fora period of 5-7 consecutive days. The patient's hemotological indiceswere lowered at least comparable to methotrexate being given at the samedoses either intravenously or orally.

[0102] Further when the cancerous tumor breaks up (after treatment aspreviously described) in many instances the liver cannot cope with thetumor toxins and debris and residue, killing the patient. Not only isthe use of hyaluronic acid with an NSAID appropriate, so is the use ofenemas employing hyaluronic acid (sodium hyaluronate) and a detoxifyingagent administered into the large bowel.

[0103] The hyaluronic acid and salts thereof may be utilized at varyingdoses—10 to 1000 mg/70 kg person with the optimal doses tending to rangebetween 50 and 350 mg/70 kg individual. As there is no toxicity, thehyaluronic acid can obviously be administered in a dose excess .(forexample 3000 mg/70 kg individual) without any adverse effects.

[0104] Thus, we have combined hyaluronic acid and/or salts thereof withcytotoxic chemotherapeutic agent, for example either administeringhyaluronic acid immediately after the agent (if the two cannot be mixedbeforehand) or having mixed the two, that is hyaluronic acid and thedrug, before administration. We have utilized for example, adriamycinadministering adriamycin prior to hyaluronic acid, methotrexate wherethe two agents are mixed together, mitomycin C, bleomycin,5-Fluorouracil, novantrone, carbo- and cis-platinum, and in all of theselatter instances the drug has been mixed directly with hyaluronic acidat a dose of 10 mg/per ml of the hyaluronic acid increasing the totaldose up to 100 mg with the standard dose of the drug in question beingutilized.

[0105] Previously, we have utilized phloridzin, phloretin, and5-deoxyglucuronide of phloridzin as agents with dimethyl sulfoxide tocompetitively block glucose transport—in neoplastic cells. These agentscan also be combined with hyaluronic acid at similar doses to thosealready mentioned for chemotherapeutic drugs where phloretin issolubilized for example by the agent N-methyl glucamine.

[0106] Thus, a treatment protocol in various different neoplasticsituations may consist of the administration of Ascorbic Acid andOncostatin IV, a combination of phloretin, solubilized in N methylglucamine, with a mixture of hyaluronic acid or salt thereof using adose of 2 to 4 grams of phloretin solubilized as described with 30 mg to1000 mgs or more (dose excess) of hyaluronic acid or sodium salt. Thishas allowed substantially enhanced penetration of the drug into tumorcells and has effected a much better result when these tumors aredeprived of glucose and then subsequently stressed either byhyperthermia, chemotherapy and/or radiation. Similarly, cytotoxicchemotherapeutic agents already mentioned have been combined withcomparable doses of hyaluronic acid and and/or salts thereofadministered either intravenously, intra-arterially, intraperitoneallyor intrapleurally or directly into the tumor by injection through aneedle placed under sonographic or CT guidance.

[0107] Intradermal delivery of other drugs may also be accomplished withhyaluronic acid and/or salts thereof: for example insulin in diabetes,estrogen in post—menopausal women, progestegens in control of fertilityand anti-metabolites for the prevention of topical infection such asthose caused by coryne bacterium acnes. They may also be applied usinghyaluronic acid.

[0108] Intravenous administration of bronchodilators may also (forexample aminophylline and theophylline) may also be accomplished withhyaluronic acid and/or salts thereof.

[0109] Enhancement of the effect of the bronchodilators byadministration with hyaluronic acid has been the result. Oraladministration with hyaluronic acid and/or salt may also be suitable.

[0110] According to another aspect of the invention, the combination ofa non-ionic surfactant for example nonoxynol-9 [nonylphenoxy polyethoxyethanol] [found in Delfen (t.m.) contraceptive cream] and hyaluronicacid and/or salts thereof and other forms is provided for treating:

[0111] (a) herpes simplex type I and type II

[0112] (b) herpes zoster (shingles) and unexpectedly provide immediaterelief of symptoms and subsequent disappearance of lesions.

[0113] The non-ionic surfactant preferably comprises an ether or anamide linkage between the hydrophilic and hydrophobic portions of themolecule, being more active than the surfactants having an ester- or anether-ester linkage.

[0114] The following nonionic surfactants and identified linkages areoffered for consideration. Surfactant Linkage None (control virus) 5%Nonoxynol-9 (nonylphenoxy-polyethoxy ethanol) Ether 1% Triton X-100(p-diisobutylphenoxy-polyethoxy- Ether ethanol) 1% Brij-97(polyoxyethylene (10) oleyl ether) Ether 1% Span-20 (sorbitranmonclamate) Ester 1% Span-80 (sorbitan moncoleate) Ester 1% Tween-20(polysorbate 20) Ether-ester 1% Tween-80 (polysorbate 80) Ether-ester 1%Onyxol 345 Amide

[0115] Where foreign objects (for example drainage tubes) must beimplanted into a human body and be left for use, it is imperative thatthe tissue surrounding the implant not become infected because once thetissue becomes infected, usually no matter how much antibiotic isadministered the infection does not clear and the implant must beremoved. Applicants have found however that where the infected tissuesurrounding the implant is treated with the antibiotic carried inhyaluronic acid (sodium hyaluronate), the infection rapidly clears andthe implant need not be removed.

[0116] Applicants have also found that in respect of treating vascularischemia (for example in cancer patients where the tumor tissue is underperfused, in patients suffering from diabetes and Berger's disease), theadministration of the medicines in hyaluronic acid (sodium hyaluronate)enhances the patient's response to the drug.

[0117] In patients suffering from brain tumors, the swelling must bereduced. Administration of dimethyl sulfoxide (DMSO) in amounts of lessthan 100 gm daily in a 10% solution in hyaluronic acid (sodiumhyaluronate)—300-500 mg reduces acute brain and spinal edema.

[0118] For the treatment of mononucleosis, Applicants have successfullyadministered to a patient suffering from a particularly bad case forsome time, Vitamin C and hyaluronic acid and the patient rapidlyrecovered.

[0119] One form of hyaluronic acid and/or salts thereof (for examplesodium salt) and homologues, analogues, derivatives, complexes, esters,fragments, and sub units of hyaluronic acid, preferably hyaluronic acidand salts and thereof suitable for use with Applicant's invention is afraction supplied by Sterivet Laboratories Limited. One such fraction isa 15 ml vial of Sodium hyaluronate 20 mg/ml (300 mg/vial—Lot 2F3). Thesodium hyaluronate fraction is a 2% solution with a mean averagemolecular weight of about 225,000. The fraction also contains water q.s.which is triple distilled and sterile in accordance with the U.S.P. forinjection formulations. The vials of hyaluronic acid and/or saltsthereof may be carried in a Type 1 borosilicate glass vial closed by abutyl stopper which does not react with the contents of the vial.

[0120] The fraction of hyaluronic acid and/or salts thereof (for examplesodium salt) and homologues, analogues, derivatives, complexes, esters,fragments, and sub units of hyaluronic acid, preferably hyaluronic acidand salts thereof may comprise hyaluronic acid and/or salts thereofhaving the following characteristics:

[0121] a purified, substantially pyrogen-free fraction of hyaluronicacid obtained from a natural source having at least one characteristicselected from the group consisting of the following: i) a molecularweight within the range of 150,000-225,000; ii) less than about 1.25%sulphated mucopoly- saccharides on a total weight basis; iii) less thanabout 0.6% protein on a total weight basis; iv) less than about 150 ppmiron on a total weight basis; v) less than about 15 ppm lead on a totalweight basis; vi) less than 0.0025% glucosamine; vii) less than 0.025%glucuronic acid; viii) less than 0.025% N-acetylglucosamine; ix) lessthan 0.0025% amino acids; x) a UV extinction coefficient at 257 nm ofless than about 0.275; xi) a UV extinction coefficient at 280 nm of lessthan about 0.25; and xii) a pH within the range of 7.3-7.9.

[0122] Preferably the hyaluronic acid is mixed with water and thefraction of hyaluronic acid fraction has a mean average molecular weightwithin the range of 150,000-225,000. More preferably the fraction ofhyaluronic acid comprises at least one characteristic selected from thegroup consisting of the following characteristics: i) less than about 1%sulphated mucopolysaccharides on a total weight basis; ii) less thanabout 0.4% protein on a total weight basis; iii) less than about 100 ppmiron on a total weight basis; iv) less than about 10 ppm lead on a totalweight basis; v) less than 0.00166% glucosamine; vi) less than 0.0166%glucuronic acid; vii) less than 0.0166% N-acetylglucosamine; viii) lessthan 0.00166% amino acids; x) a UV extinction coefficient at 257 nm ofless than about 0.23; xi) a UV extinction coefficient at 280 nm of lessthan 0.19; and xii) a pH within the range of 7.5-7.7

[0123] Other forms of hyaluronic acid and/or its salts, and homologues,derivatives, complexes, esters, fragments and sub units of hyaluronicacid may be chosen from other suppliers, for example those described inthe prior art documents previously referred to. In addition Applicantshave successfully employed sodium hyaluronate produced and supplied byLifeCore™ Biomedical, Inc. having the following specificationsCharacteristics Specification Appearance White to cream coloredparticles Odor No perceptible odor Viscosity Average <750,000 DaltonsMolecular Weight UV/Vis Scan, 190-820 nm Matches reference scan OD, 260nm <0.25 OD units Hyaluronidase Sensitivity Positive response IR ScanMatches reference pH, 10 mg/g solution 6.2-7.8 Water 8% maximum Protein <0.3 mcg/mg NaHy Acetate <10.0 mcg/mg NaHy Heavy Metals, maximum ppm AsCd Cr Co Cu Fe Pb Hg Ni 2.0 5.0 5.0 10.0 10.0 25.0 10.0 10.0 5.0Microbial Bioburden None observed Endotoxin <0.07 EU/mg NaHy BiologicalSafety Testing Passes Rabbit Ocular Toxicity Test

[0124] The following references teach hyaluronic acid, sources thereofand processes of the manufacture and recovery thereof.

[0125] U.S. Pat. No. 4,141,973 teaches hyaluronic acid fractions(including sodium salts) having:

[0126] “(a) an average molecular weight greater than about 750,000,preferably greater than about 1,200,000—that is, a limiting viscositynumber greater than about 1400 cm³/g., and preferably greater than about2000 cm³/g.;

[0127] (b) a protein content of less than 0.5% by weight;

[0128] (c) ultraviolet light absorbance of a 1% solution of sodiumhyaluronate of less than 3.0 at 257 nanometers wavelength and less than2.0 at 280 nanometers wavelength;

[0129] (d) a kinematic viscosity pf a 1% solution of sodium hyaluronatein physiological buffer greater than about 1000 centistokes, preferablygreater than 10,000 centistokes;

[0130] (e) a molar optical rotation of a 0.1-0.2% sodium hyaluronatesolution in physiological buffer of less than −11×10³ degree—cm²/mole(of disaccharide) measured at 220 nanometers;

[0131] (f) no significant cellular infiltration of the vitreous andanterior chamber, no flare in the aqueous humor, no haze or flare in thevitreous and no pathological changes to the cornea, lens, iris, retina,and choroid of the owl monkey eye when one milliliter of a 1% solutionof sodium hyaluronate dissolved in physiological buffer is implanted inthe vitreous replacing approximately one-half the existing liquidvitreous, said HUA being

[0132] (g) sterile and pyrogen free and

[0133] (h) non-antigenic.”

[0134] Canadian Letters Patent 1,205,031 (which refers to U.S. Pat. No.4,141,973 as prior art) refers to hyaluronic acid fractions havingaverage molecular weights of from 50,000 to 100,000; 250,000 to 350,000;and 500,000 to 730,000 and discusses processes of their manufacture.

[0135] Where high molecular weight hyaluronic acid (or salts or otherforms thereof) is used, it must be diluted to permit administration andensure no intramuscular coagulation.

[0136] One formulation of Ascorbic Acid (Vitamin C) injection USP ismanufactured by Steris Laboratories, Inc., Phoenix, Ariz., 85043 U.S.A.and comprises 22 mg/ml (equivalent to sodium ascorbate 250 mg/ml) in 30ml, 50 ml, or 100 ml individual containers, 30 ml size being preferred.

[0137] Thus Applicant has combined hyaluronic acid (and sodiumhyaluronate and/or other forms) with medicinal and/or therapeutic agentsfor the treatment of conditions and diseases with totally unexpectedresults:

[0138] For Example Condition/Disease Chemicals & Drugs 1. Cancer,increasing activity free radical scavenger, of macrophages superoxidedismutase, ascorbic acid (Vitamin C) anti-cancer drugs, NSAID,Chemotherapeutic Agents, detoxifying Agents (e.g. cholestyramine) 1A.Reduction of swelling Dimethyl Sulfoxide (DMSO) in brain of personsuffering brain trauma 2. Hair growth minoxidil - combination - growmore hair when applied- topically 3. Herpes, canker sore, nonionicsurfactants, e.g., shingles nonoxynol-9 and anionic, (e.g. cetylpyridinium chloride) and cationic (e.g. benzalkonium choride),surfactants 4. Renal failure, cardiac diuretics - furosemideinsufficiency, hypertension, edema 5. Infection, acne, antibiotics,antibacterials, mononucleosis antimicrobials, etc., ascorbic acid andhyaluronic acid 6. Transplants cyclosporins 7. Inflammation, eliminationof non-steroidal anti-inflamma- tumor break down material tories, NSAIDe.g. (toxins and debris), diclofenac, decreasing side effects,indomethacin, piroxicam, relief of pain (e.g. ibuprofen, tromethaminesalt back pain) of Ketorolac, naproxen, 8. Detoxification enema,,detoxifying agent, peritoneal dialysis 9. Bronchodilationbronchodilators, e.g. beclo- methasone diproprionate (sodiumcromoglycate although not specifically a broncho- dialator),theophylline 10. Vascular ischemia treat limbs in respect of diabetes,Berger's disease, etc. with suitable medicine e.g. Trental 11. HIV(AIDS) DMSO, Vitamin C, NSAID (e.g. indomethacin, naproxen, ketorolactromethamine), interferon, Vibramycin ™, (doxcycline), tetracycline -12. Diabetes insulin 13. Post-menopause estrogens replacement 14.Prevention of topical antimetabolites (e.g. infection sulfonamides) 15.Reduction of swelling DMSO 16. Hypertension, cardiac Calcium channelblockers e.g. - insufficiency Nifedipine β-Blockers e.g. atenolol,propranolol 17. Prostaglandin acetylsalicylic acid Synthesis inhilition18. Enhance oxygenation of perfusate tissue by perfusion fluid bathingthe tissue (for transplantation purposes

[0139] In respect of the treatment of cancer particularly, Applicantshave now provided a method of treatment and combinations of chemicalsand drugs which appear to enhance a patient's life expectancy andquality of life (even those patients not responding to the usualtreatments). Applicants have successfully treated patients with theirinvention, increasing the rate of tumor destruction, improving forexample macrophage function, to enable the body to eliminate the tumorcells, dead tumor waste, debris, and toxins.

EXAMPLES

[0140] The following examples are offered to illustrate Applicants'invention. In substantially all, if not all cancer cases, the patienthad been unresponsive to conventional treatment. The hyaluronic acidreferred to herein also includes other forms—for example sodiumhyaluronate.

[0141] Case I:

[0142] A 59 year old male with a laryngeal epidermoid (squamous typetumor) treated in its primary state with a combination of surgery andradiation developed metastatic disease in the liver some seven yearslater. Two major tumors were noted at a size of 12 cm and 6 cm diameter.These were treated with combination therapy using systemic chemotherapywith added DMSO to enhance penetration, phloretin

[0143] solubilized by N methyl glucamine with added DMSO to enhancepenetration and the direct administration of

[0144] adriamycin, carboplatinum and methotrexate into the tumor bysystemic and intratumor injection therapy but in this case but withadded hyaluronic acid at a dose of 10 to 60 mgs for the different drugs.This was achieved without any adverse effects and the patient wasreassessed four weeks later. At that point in time the smaller tumor haddisappeared entirely. The larger tumor was apparent only as a necroticfocus measuring now 5 cm in diameter but no apparent surviving tumorcould be detected by examination and needle biopsy. This caseillustrates the superior effect of hyaluronic acid on penetration ofdrug thus allowing better tumor destruction.

[0145] Follow-Up

[0146] Subsequently patient was given treatment of Indomethacin 300 mgand 300 mg Hyaluronic Acid daily; patient was in remission, howeverpatient died of infection at a later date.

[0147] Case II:

[0148] A 42 year old female developed malignant melanoma with tumorpresent in the left upper thigh and inguinal nodes, the abdominal cavityand liver, lungs, and the base of the brain affecting involvement ofvarious cranial nerves. Her primary tumor had been excised and she haddeveloped recurrent disease which was deemed untreatable as there is nocytotoxic or cytostatic chemotherapy that has major effects on thistumor when it is as widespread as observed in this patient. The patientwas treated with a combination of phloretin solubilized in N methylglucamine with added hyaluronic acid at a dose of 10 to 50 mg/2 to 4grams administered intravenously and this agent was given for five daysover 4-24 hours/day. She also received hyperthermia to the various areasof the tumor and concomitant systemic therapy with carboplatinum withadded hyaluronic acid at a dose of 250 mg carboplatinum total plusmethyl CCNU administered at a total dose of 120 mg over 5 days orallywhile the patient received hyaluronic acid systemically. Methotrexatemixed with hyaluronic acid was injected into the tumor which could bepalpated in the left thigh or inguinal region at a dose of 37.5 mg with60 mg of hyaluronic being added, the doses being divided equally at twodifferent days by injection. The patient responded over the next 10 to20 days with dramatic and total regression of the upper thigh andinguinal tumors, dramatic improvement in liver function with the tumorsin the liver becoming cystic (generally regarded as a sign of tumorbreak down) and disappearance of the lung tumors. The tumor at the baseof the brain regressed as manifested by improvement of her cranial nervefunction and a decrease of pain and headaches. In this patient a tumorwhich is unresponsive to the majority of agents at this phase ofdevelopment was made markedly responsive when the same agents were usedwith hyaluronic acid as a penetrating agent.

[0149] Follow-Up

[0150] The patient was subsequently given treatments of phloretin,indomethacin (NSAID) and hyaluronic acid. This patient is now incomplete remission.

[0151] Case III:

[0152] A 55 year old female patient with cancer of the gallbladderoccupying the entire right lobe of the liver. This patient had beentreated on three previous occasions with a combination of heat, systemicchemotherapy with added DMSO, phloretin with added DMSO and directinjection of cytotoxic drugs with added DMSO. Beginning May 1989 she wastreated with the comparable drugs with added hyaluronic acid as acarrier or dispersing molecule administered both systemically and bydirect injection into the tumor. The tumor which had shrunk marginallyby approximately 20% prior to this now reduced in size dramatically byover 50% and continues to diminish in size. This tumor is judgedunresponsive to these drugs alone when administered by the normalroutes.

[0153] Follow-Up

[0154] Unfortunately the patient relapsed, became depressed and died.

[0155] Case IV:

[0156] A 55 year old female with cancer of the colon metastatic to theliver with one major large tumor mass occupying the entire right lobe ofthe liver and medial segment of the left lobe extending into the l leftlobe and judged unresectable by a hepatic surgeon two months earlier wastreated with systemic chemotherapy and injection of chemotherapeuticagents directly into the tumor plus phloretin solubilized with N methylglucamine with hyaluronic acid and hyperthermia. The patient had a threeday course of therapy and was injected on one occasion directly into thetumor with cytotoxic drugs and hyaluronic acid and reassessed threeweeks later. Sonographic examination showed total liquafaction of thetumor leaving only a small rim of apparently viable tissue; 500 ccs ofamber colored fluid with necrotic tumor tissue present was drained fromthe now cystic lesion. This is an unusual and dramatic response for anadenocarcinoma which generally responds extremely slowly. It is judgedthat less than 30% of these patients achieved any significant diseaseregression utilizing standard cytotoxic or cytostatic chemotherapy. Theenhanced destruction here occurring over three weeks and is judged asdue to the use of the carrier penetrating molecule, hyaluronic acid.

[0157] Follow-Up

[0158] From the examinations, there was total tumor necrosis. Thepatient however died some time later of liver failure and pulmonaryembolism.

[0159] Case V:

[0160] A 53 year old man with transitional cell cancer of the bladder ina very advanced state of his disease with metastases involving theentire left pelvis, extending to the periaortic and parapancreatic andsupraclavicular nodes having recurred after previous surgical excision,radiation and having not responded by major regression to standardchemotherapy was treated using phloretin solubilized in N-methylglucamine with added hyaluronic acid with a direct injection ofcarboplatinum and methotrexate into the tumor tissue. Hyperthermia tothe areas of the tumor was also applied. The patient developed adramatic response and developed a febrile reaction due to tumor breakdown and release of bacteria. This reaction was controlled byantibiotics and appropriate hydration and as the patient was observedthrough this phase a dramatic decrease in the size of the tumor wasobserved on an almost daily basis with an over 50% reduction in tumorsize having occurred by 7 days after therapy. This is a remarkable anddramatic response of a tumor which at this phase had been judged asunresponsive to all therapy and it is thought to be due to the use ofthe drug which blocks glucose transport employed here with a carrier andpenetrating molecule, hyaluronic acid and chemotherapy administereddirectly into the tumor with the same agent.

[0161] Follow-Up

[0162] There was, as a result, total tumor necrosis. However at a laterdate, the patient died of an infection.

[0163] Case VI:

[0164] This patient had a right upper lobe lesion diagnosed, confirmedby biopsy and deemed not surgically resectable. This tumor, according todocumentation utilizing chemotherapy or radiotherapy has a zero responserate. He was treated with systemic chemotherapy in hyaluronic acid asfollows: DATE DRUG DOSE 05/10 vinblastine 3 mg 05/10 mitomycin 3 mg05/10 calcium leukovorin 40 mg 05/10 5fluorouracil 250 mg 05/105fluorouracil 250 mg 05/10 Oncostatin IV 3 mg Hyaluronic Acid III 10 mg05/11 carboplatin 250 mg 05/11 vinblastine 5 mg 05/11 mitomycin 4 mg05/11 calcium leukovorin 40 mg 05/11 5fluorouracil 250 mg 05/115fluorouracil 250 mg 05/12 carboplatin 100 mg 05/12 vinblastine 2 mg05/12 5fluorouracil 250 mg 05/12 5fluorouracil 250 mg 05/12 calciumleukovorin 40 mg 05/12 Oncostatin IV 2 mg Hyaluronic Acid 20 mg 06/19mitomycin 5 mg Hyaluronic Acid 10 mg 06/19 vinblastine 5 mg HyaluronicAcid IV 10 mg 06/19 5fluorouracil 250 mg Hyaluronic Acid IV 10 mg 06/195fluarouracil 250 mg Hyaluronic Acid IV 10 mg 06/19 calcium leukovorin40 mg 06/19 Oncostatin IV 3 mg Hyaluronic Acid 50 mg 06/20 5fluorouracil250 mg Hyaluronic Acid IV 10 mg 06/20 5fluorouracil 250 mg HyaluronicAcid IV 10 mg 06/20 calcium leukovorin 40 mg 06/20 mitomycin 5 mgHyaluronic Acid IV 10 mg 06/20 vinblastine 5 mg Hyaluronic Acid IV 10 mg06/20 Oncostatin IV 3 m Hyaluronic Acid IV 50 mg 06/21 Carboplatin 20 mgHyaluronic Acid IT 10 mg 06/21 methotrexate 12.5 mg 06/21 carboplatin150 mg Hyaluronic Acid IV 50 mg Oncostatin IV 3 mg Hyaluronic Acid IV 50mg 06/22 carboplatin 100 mg Hyaluronic Acid IV 10 mg 06/22 Oncostatin IV3 g Hyaluronic Acid IV 50 mg 06/23 Oncostatin IV 3 g Hyaluronic Acid IV50 mg 08/16 calcium leukovorin 40 mg 08/16 5fluorouracil 500 mgHyaluronic Acid IV 50 mg 08/16 carboplatin 250 mg Hyaluronic Acid IV 100mg Oncostatin IV 3 g Hyaluronic Acid IV 100 mg 08/17 carboplatin 200 mgHyaluronic Acid IV 150 mg 08/17 carboplatin 30 mg Hyaluronic Acid IV 50mg 08/17 adriamycin 2.5 mg Hyaluronic Acid 10 mg Oncostatin 3 gHyaluronic Acid 100 mg 08/18 5fluorouracil 500 mg Hyaluronic Acid 100 mg08/18 calcium leukovorin 40 mg Oncostatin IV 2 g Hyaluronic Acid 200 mg

[0165] He was also treated with phloretin in hyaluronic acid. His tumorwas injected with the following chemotherapeutic agents in hyaluronicacid: DATE DRUG DOSE 05/11 methotrexate 12.5 mg hyaluronic acid 50 mgadriamycin 1 mg 06/21 methotrexate 12.5 mg carboplatin 20 mg hyaluronicacid 10 mg 08/18 carboplatin 30 mg hyaluronic acid 50 mg 08/18adriamycin 25.5 mg hyaluronic acid 10 mg

[0166] He has had regression of his disease by 50 per cent in asituation that is otherwise not treatable. This therefore documents thatunresponsive tumors can respond to chemotherapy when administered inhyaluronic acid and/or salts thereof.

[0167] Case VII:

[0168] Female patient, aged 58, had a massive cancer of the breast withsupraclavicular and auxiliary lymph nodes palpable. This has beenconfirmed by a biopsy. She was treated with combination systemic therapyand hyperthermia and did not improve significantly. She then receivedradiation from December, 1988 to January, 1989. She. was subsequentlyseen again by Dr. Falk on May 17, 1989 and had not had a response totherapy to date. She then developed a plural effusion. She was treatedby Dr. Falk by a combination of chemotherapeutic agents as follows:(Hyaluronic Acid may be Sodium Hyaluronate) DATE DRUG DOSE 05/16methotrexate 25 mg Hyaluronic Acid IT 10 mg 05/16 methotrexate 25 mgHyaluronic Acid axilla IT 10 mg 05/16 methotrexate 25 mg Hyaluronic AcidSC node IT 10 mg 05/16 Oncostatin IV 3 g Hyaluronic Acid 20 mg 05/175fluorouracil 250 mg 05/17 5fluorouracil 250 mg 05/17 vinblastine 5 mg05/17 mitomycin 5 mg 05/17 Oncostatin IV 3 mg Hyaluronic Acid 30 mg06/02 methotrexate 25 mg Hyaluronic Acid IT 30 mg 06/02 vinblastine 5 mgHyaluronic Acid IV 10 mg 06/02 Oncostatin IV 3 g Hyaluronic Acid 30 mg06/05 5fluorouracil 250 mg Hyaluronic Acid IV 10 mg 06/05 5fluorouracil250 mg Hyaluronic Acid IV 10 mg 06/05 calcium leukovorin 35 mg 06/05vinblastine 5 mg Hyaluronic Acid IV 10 mg 06/05 Oncostatin IV 3 gHyaluronic Acid 30 mg 06/21 carboplatin 20 mg Hyaluronic Acid IT 10 mg06/21 methotrexate 12.5 mg 06/21 vinblastine 5 mg Hyaluronic Acid IV 10mg 06/21 mitomycin 5 mg Hyaluronic Acid IV 10 mg 06/21 Oncostatin IV 3mg Hyaluronic Acid 50 mg 07/10 carboplatin 25 mg Hyaluronic Acid IT 20mg 07/10 methotrexate 12.5 mg Hyaluronic Acid IT 20 mg 07/10 OncostatinIV 3 g Hyaluronic Acid 50 mg 07/12 Oncostatin IV 2 g Hyaluronic Acid 50mg 08/14 vinblastine 5 mg Hyaluronic Acid IV 50 mg 08/14 5fluorouracil50 mg Hyaluronic Acid IV 50 mg 08/14 calcium leukovorin 30 mg 08/14Oncostatin IV 3 g Hyaluronic Acid 100 mg 08/16 Oncostatin IV 3 gHyaluronic Acid 100 mg

[0169] She had also had a thoracentesis with subsequent instillation of5fluorouracil, mitomycin C and hyaluronic acid into the chest cavity.Her pleural effusion is totally resolved. The lesions in her breastcontinue to recede and her supraclavicular and axillary lymph adenopathyis totally gone.

[0170] This patient represents a response with relatively low doses ofhyaluronic acid and/or salts thereof added to conventional chemotherapyused systemically by injection into the tumor and by intra-pleuralcavity instillation. The response has been further enhanced by the useof phloretin in synacid T.M. (hyaluronic acid and/or salts thereof) atthe same time.

[0171] Follow-Up

[0172] At a much later date this patient is in remission and doing verywell.

[0173] Case VIII:

[0174] This is a 62 year old female treated previously with systemicchemotherapy, two different drug combinations without any response. Shewas referred for treatment including hyperthermia, and directchemotherapy injections to which she responded initially, beginningSeptember.

[0175] She was noted in April-May, to have an increase in the tumour inthe right upper lobe of her lung. This tumour was an anaplastic smallcell carcinoma. The tumour was treated by injecting into the lesionbleomycin with hyaluronic acid and indomethacin with hyaluronic acid.She also received systemically indomethacin 300 mg daily with 300 mghyaluronic acid. The patient was followed radiologically and improvedvery dramatically over the next 2 to 4 weeks. The last film report showsthat the left hemi-thorax is clear. On the right side there is noevidence of pleural reaction. There is a prominent right upper lobevolume loss with elevation of the right hilum. The area of(increasedlucency in the right apex may represent a region of cavitation withinthe collapsed lobe or elevation of the superior segment of the rightlower lobe. Comparison with previous films shows that the mass hasdecreased significantly in size and cannot now be distinctly identifiedon this examination.

[0176] The applicants believe that this response is a direct result ofthe carrier molecule—hyaluronic acid—injected with a chemotherapeuticagent and with a non-steriodal anti-inflammatory drug to assist inclearance of the necrotic tumour.

[0177] Case IX:

[0178] This patient was diagnosed as having a gastric cancer July, 1988and it was deemed unresectable. A gastroenterostomy-type of bypass wasperformed. Saw the patient initially in August and treatment wasinitiated in September, 1988. At that time he was heated and receivedphloretin with very low dose chemotherapy employing 5-FU plus immuneaugmenting agents.

[0179] This therapy essentially was continued until February, 1989 whenDr. Falk began to use DMSO as a carrier/penetrating agent in addition toMSN. He did receive increasing amounts of chemotherapy employing 5FUleukovorin, mitomycin C and methotrexate and subsequently in July andearly August, as there was tumor progression, he also receivednovantrone.

[0180] As of May he began to receive these drugs in hyaluronic acid butthe initial amounts of hyaluronic acid were small, employing 10-30 mgper average dose with the original drug i.e. phloretin, or thechemotherapeutic agent. There was some initial improvement in his statusbut then in mid August he progressed to a situation where there wasincreasing evidence of gastric obstruction, and also obstruction of thebiliary tree with jaundice and elevation of the bilirubin. Dr. Falk thentreated with higher doses of hyaluronic acid to a total dose of 500-600mg of hyaluronic acid divided among the different drugs. The patientcontinued to receive the same types of drugs.

[0181] While his condition initially deteriorated, an uppergastro-intestinal series performed on September the 7th shows hisgastric bypass to be totally open whereas prior to this the patient hadbeen vomiting all oral intake. His status has now steadily improved.

[0182] On the basis that the patient received identical drugs earlier,the improvement must be. attributed to the higher doses of the carriermolecule, allowing for better penetration of drug into what is always ascarred, fibrotic tumor and generally fatal at this stage.

[0183] Follow-Up

[0184] Unfortunately at a subsequent date, patient died as a consequenceof tumor necrosis and scar tissue developing—not from cancer.

[0185] Case X:

[0186] Patient was diagnosed as having a hepatoma now over 2 years age.The tumor had been stable or with minimal growth over the past 18months. Since treatment with low dose chemotherapy and thecarrier/penetrating molecule, hyaluronic acid, she appears to have had acomplete response. Her alkaline phosphatase is now at 150 internationalunits and the remainder of her liver function tests are essentiallynormal. Her ultrasound show no distinct tumors anymore in the liver. Dr.Falk is now treating her once every 2-3 months.

[0187] Follow-Up

[0188] This patient is still doing well.

[0189] Case XI:

[0190] This patient was infused on Jun. 15, 1989 with chemotherapy withadded hyaluronic acid on one occasion. She then received hyperthermia.Previously with multiple hepatic metastases from cancer of the breastshe had been stable on tamoxifen, the estrogen-blocking substance.

[0191] After one course of infusion of only 8 hours she has had whatwould appear to be a complete response. Her ultrasound now shows notumor present in the liver and her liver function tests are all normal.

[0192] For the present no further treatment necessary are following herand continuing her on tamoxifen to block the estrogen receptor.

[0193] Follow-Up

[0194] This patient relapsed after another doctor gave vaginal estrogencream (tamoxifen) to her for vaginal irritation. In response, patientwas given treatments of 300 mg of indomethacin in 300 mg of hyaluronicacid daily. She is now in remission.

[0195] Case XIA:

[0196] This patient had a massive leomyosarcoma of the uterus resectedon Mar. 26, 1989. There was residual tumor present as demonstrated by aCAT scan. Dr. Falk has treated her with a combination of hyperthermia,very low dose methotrexate using this intraperitonealy with acarrier/penetrating molecule—hyaluronic acid and then using the agentthat blocks glucose transport protein—phloretin, also with hyaluronicacid and alpha II interferon intraperitonealy again combined withhyaluronic acid.

[0197] On sequential CT scan this patient shows significant improvementin size of the residual mass. As soft tissue sarcomas are so veryresistant to all forms of therapy this. could be described as an unusualresponse and is in all likelihood related to the use of thecarrier/penetrating molecule—hyaluronic acid. Dr. Falk is now treatingthis patient approximately every 6-8 weeks for 2 days and hopefully herregression of tumor will continue. If that is the case, than one couldconsider closing her colostomy in about 6 month's time.

[0198] Follow-Up

[0199] Some tumor grew back. Patient was given treatments of Vitamin C(50 mg daily), indomethacin (300 mg daily) in 300 mg of hyaluronic acid.This patient is feeling much better.

[0200] Case XIB:

[0201] This patient has received relatively low doses initially ofmethyl CCNU and carboplatin with methotrexate injected into the inguinalrecurrent melanoma. All of these molecules were given in thecarrier/penetrating agent hyaluronic acid. In addition she received theagent that blocks glucose transport which Dr. Falk has developed. Thisis a molecule called phloretin which was used many years ago. It hasbeen solubilized in a special solution and is also given with hyaluronicacid as it will also enhance the penetration of this molecule into thetumor. Dr. Falk then treated her with hyperthermia using both capacitiveand inductive radio frequency hyperthermia and microwave hyperthermia.In addition she has received immune stimulating agents which Dr. Falkbelieves will produce benefit but only in conjunction with other agents.

[0202] In the last 2 courses of treatment she has received onlycarboplatin with added hyaluronic acid, phloretin with added hyaluronicacid and methotrexate administered now by intra-peritoneal route at alow dose—25-35 mg in hyaluronic acid again.

[0203] Dr. Falk saw her this week and he will treat her for 2 days. Sheis clinically in excellent condition. She has. the one complaint ofright-sided back pain. On examination one does have the impression thatthis could be tenderness over the right kidney. The ultrasounds of herkidneys have suggested a solid mass in the right kidney which wasinterpreted as being either a hamartoma or even an angiomyolipoma.

[0204] In view of the patient's rather dramatic response Dr. Falk thinksit would be worth while to get a CAT scan done of the abdomen. There isstill the question of a small cystic lesion in the right lobe of theliver but her liver function in now normal.

[0205] Follow-Up

[0206] This patient is now in complete remission.

[0207] Case XII:

[0208] The patient had an arterial line and subcutaneous port installedat the time of the original abdominal surgery. He came to see Dr. Falkand it was noted that there was redness, in duration and swelling aroundthe subcutaneous port. The patient had a febrile response and elevationof his leukocytes.

[0209] A £ 14 gauge plastic cannula was inserted into the area and 75 ccof purulent material was drained and cultured growing E. coli andPseudomonas aeruginosa. Dr. Falk treated him by irrigating the site witha combination of hyaluronic acid with ampicillin, hyaluronic acid withflagyl., and hyaluronic acid with keflosporin. Thus the wound wasirrigated on a daily basis with 1 gram of ampicillin with 50 mgs. ofhyaluronic acid, 500 mgs. flagyl with 50 mgs. of hyaluronic acid and 1gram of Ancef with hyaluronic acid. During the first 2-3 days irrigationit was possible to continue to aspirate purulent material from thesubcutaneous site. Within 5 days there,was no purulent materialremaining and there was just fluid present and by the end of the weekthere was no residual infection present. The port-a-cath continued tofunction over the next three months of the patient life.

[0210] This is cited as an example of anti-bacterial agents with addedhyaluronic acid producing better penetration of the various differentanti-bacterial drugs into the site of infection and one would have topostulate that there was improved penetration into the bacteriathemselves.

[0211] Case XIII:

[0212] This patient was operated on Jun. 1, 1989 and a resection wasperformed of a portion rectum and sigmoid colon, and the smallintestine. Post-operatively on day 7 he was noted to have swelling andinduration in the wound tissue and two sites of purulent material weredrained. He was treated subsequently with local irrigation withampicillin 1 gram combined with 50 mgs. hyaluronic acid and 500 mgs. offlagyl combined with hyaluronic acid. These two areas of infectioncleared of any bacterial contamination within 4 days. The usual timerequired would be in the order of a number of weeks.

[0213] Case XIV:

[0214] This patient with cancer of the breast has an infected HickmanLine. This is an indwelling plastic catheter in the subclavian vein.This infection was present subcutaneously with purulent material comingfrom the site of the entry of the plastic cannula. In this situation Dr.Falk injected ampicillin 1 gram and 50 mgs. of hyaluronic acid directlyadjacent to the plastic catheter. In addition the patient receivedflagyl intravenously with added hyaluronic acid. The infection clearedand the catheter was presented in a matter of 4 days.

[0215] Case XV:

[0216] This man developed an abscess on the right upper quadrant of hisabdomen, in the anterior abdominal wall. This was drained in hospitalbut continued to be a problem. Dr. Falk has now discharged him and begunto irrigate this with ampicillin 500 mg daily and 200 mg of hyaluronicacid. While this abscess was drained and therefore should have recoveredeventually, it had taken a longer period of time than one would haveanticipated. The abscess grew both staphlyococcus aureus and e. coli.

[0217] After 2 days of irrigation with ampicillin and hyaluronic acid asdescribed, the cavity was clean, free of infection and beginning togranulate over nicely. Dr. Falk continued to treat him during the weekand it healed satisfactorily.

[0218] In other patients alpha 2-interferon was combined with hyaluronicacid and applied to a patients canker sores and the sores rapidlycleared up.

[0219] In another patient, methotrexate was carried in hyaluronic acidand applied topically to a patient with psoriasis. The formulation wasabsorbed and the psoriasis cleared.

[0220] In ten other patients suffering from herpes simplex type I andII, the application of an effective amount of nonoxynol-9 [nonylphenoxypolyethoxy ethanol] (Delfen™) combined with hyaluronic acid and/or saltsthereof to the effected areas 2 to 3 times daily gave immediate reliefof the symptoms (pain) and disappearance of the lesions.

[0221] In at least two patients, an effective amount of nonoxynol-9 fortreating herpes zoster (shingles) was combined with hyaluronic acidand/or salts thereof and was successfully employed to treat the herpeszoster (shingles)

[0222] Case XVI:

[0223] A dentist with melanoma, age 51, developed acute herpes zoster inthe 9th thorasic dermital on the left side of his body. He was inexcruciating pain, not relieved by classical medications. Dr. Falk askedhim to take orally cyclofur as an antiviral but he did not begin thisimmediately. However, Dr. Falk also indicated that he should take“Delfen™” and “LifeCore™” hyaluronic acid, mix equal portions and thenapply this topically. He did this and had immediate relief of painwithin 5 minutes. The pain has. remained absent for the next 4 days. Inaddition, the lesions of herpes zoster immediately began to disappearwithin the first 24 hours and now, 5 days later, none are apparent. Thisis a dramatic response suggesting a major antiviral affect of thiscombination, with the hyaluronic acid obviously enhancing penetration.

[0224] Case XVII:

[0225] This man developed stomach cancer which metastasized to hisliver. He was treated for seven months with low dose chemotherapy (5FU), low doses of mitomycin and novantrone with various amounts ofhyaluronic acid, and Vitamin C (50 gm daily). There was no detectabletumor. He is now in remission and all tumors are calcified.

[0226] Case XVIII:

[0227] This male patient had a serious car accident, shortly thereafterhe developed colon cancer which was resected with multiple livermetastases. He came to Dr. Falk in June, 1989. He was treated withchemotherapy (phloretin) and hyaluronic acid with heat. He remainedstable for approximately one year, then his alkaline phosphatase began“creeping up”. Consequently, Dr. Falk treated him with Vitamin C (50 gmdaily for three days), hyaluronic acid (up to 300 mg daily),indomethacin in N-methyl glucamine (300 mg daily in the 300 mg ofhyaluronic acid), and Toradol™ (60 mg) once or twice daily withhyaluronic acid (50 mg). Since that time he has shown improvement. Hisalkaline phosphatase decreased, and therefore his liver is functioningbetter.

[0228] Case XIX:

[0229] This man, age 46, was diagnosed in the last three months with adifficult to treat broncheolar alveolar carcinoma of the lung.Appropriately, neither chemotherapy nor major amounts of radiation wereused, although spot radiation was given to two areas; one on either sideof the chest where there apparently was some indication of skeletalinvolvement.

[0230] Subsequent to that, the patient visited a cardio-pulmonarytransplant unit in London who thought that a transplant might beappropriate but there was a waiting list of about one year.

[0231] After this the patient went to Dr. Frederick Douwe's clinic inGermany and was placed on a variety of regimens, the main direction ofwhich includes; (a) immune enhancement at the T-cell level; and (b) freeradical scavenging and detoxification.

[0232] He has improved somewhat since this treatment was initiated withepisodes when he is very short of breath, having had one of those 24hours. ago.

[0233] On examination he has very severely diminished air entry on bothsides with bilateral rales and ronchi. There is no evidence ofsupraclavicular adenopathy. There is no evidence of skeletal tendernessat this point or of hepatic enlargement.

[0234] He then came to Dr. Falk and he treated him with Vitamin C (50gms), non-steroidal indomethacin (NSAID)(100 mg—reduced from initialamount of 300 mg because of heartburn) dissolved in hyaluronic acid (300mg). He improved dramatically after the first 5 days of therapy withreference to lung capacity and radialogical appearance on the X-ray.

[0235] Dr. Falk then prescribed daily injections of hyaluronic acid (300mg) with Toradol™ (60 mg) to be taken at home (“home” being outside ofCanada).

[0236] Comparison has been made to the previous examination. Since thatprevious examination, there has been resolution of some of the increasedinterstitial markings so that the lungs now look clearer than they didon the previous exam. Nonetheless, increased interstitial markings arestill present within both lung fields.

[0237] Case XX:

[0238] A female patient, age 74, was diagnosed with cancer of the colonand was resected. The cancer had however mestastasized to the liver(right lobe). Over a one month period, she was treated twice withmethotrexate (25 mg) in hyaluronic acid (400 mg) intraperitoneally, fivetimes with oncostatin (2 gm) in hyaluronic acid (300-500 mg), Vitamin C(50 gm) in hyaluronic acid (300 mg), and indomethacin (NSAID) giventwice, 100 mg of indomethacin in 300 mg hyaluronic acid and 250 mg ofindomethacin in 500 mg of hyaluronic acid.

[0239] The patient is now doing very well, feeling better, and the livertumor is regressing (shrinking).

[0240] Case XXI:

[0241] This female patient, age 51, was diagnosed with cancer of *theuterus which had spread to the lungs (leiomyosarcoma). Dr. Falk treatedher with various doses of oncostatin (low doses of 0.5 gm to 3 gm) withhyaluronic acid (300-500 mg), Vitamin C (50 gm) in hyaluronic acid (300mg), and indomethacin in hyaluronic acid (intraperitoneally andintravenously).

[0242] The pelvic mass is presently regressing and the lungs are nowstable.

[0243] Case XXII:

[0244] This man, age 52, has a history of Crohn's Disease and chronicinfection in the bowel from Crone's disease. He eventually developed atumor in the peritoneum (adenocarcinoma). The patient was treated withdoses of 2 gm and 3 gm of Oncostatin™ (phloretin) each in hyaluronicacid (500 mg) and DMSO (total of 2000). Doses of indomethacin rangingfrom 75 mg to 450 mg in 200 to 700 mg of hyaluronic acid were given.Patient was also treated with Vitamin C (50 gm) in hyaluronic acid (300mg), and naproxen (1 gm) in hyaluronic acid (400 mg). These treatmentswere given to the patient via several routes intraperitoneally,intravenously, rectally (for detoxification) (insertion of catheter andadministered rectally). The pain is now gone.

[0245] Patient was given CT Scan of the abdomen and pelvis. There ismoderate hepatic steatosis without evidence of metastatic disease. Thespleen, pancreas, adrenals and right kidney appear normal. There is aleft nephrostomy tube in place with no evidence of residualhydronephrosis. There is a large and necrotic tumor mass occupying mostof the deep pelvis with anterior displacement of the urinary bladder andlikely some invasion of the prostate gland. There is no evidence ofsacral destruction although the rectal tumor is closely apposed to itsanterior surface.

[0246] Thus there appears to be a large and necrotic pelvic tumor masswithout evidence of sacral destruction, para-aortic lymphadenopathy ordistal visceral metastases. A left percutaneous transrenal ureteralstent is in place.

[0247] The patient was seen Aug. 1, 1990, in the clinic and he has beenfeeling very well. He is doing extremely well; the necrotic tumor massis slowly reducing in size.

[0248] Case XXIII:

[0249] This female patient, age 47, was diagnosed in January, 1990. Agastric resection and colonic replacement of oesophagus (for swallowing)was performed. She had also developed an intraperitoneal tumor. She wasgiven chemotherapy and lost her hair. (Dr. Falk gave her minoxidil andhyaluronic acid to apply to her scalp and her hair grew back). Dr. Falksaw this patient on Jun. 6, 1990, and gave her lower doses of phloretintogether with heat and hyaluronic acid, indomethacin in hyaluronic acid,and Vitamin C in hyaluronic acid.

[0250] Since the time of treatment, the patient has made goodimprovement. She has gained weight, and is no longer feeling any pain.The carcinoembryonic antigen is down to 26 nonograms/ml and steadilyfalling.

[0251] Case XXIV:

[0252] This man (age 45) first seen by Dr. Falk on Mar. 1, 1988, he wasdiagnosed with carcinoma of the pancreas. He was treated with DMSO andheat together with low doses of chemotherapy. Dr. Falk injected the DMSOand the other drugs into the tumor. More than one year later, thispatient was given treatments with Vitamin C, and other agents inhyaluronic acid. This patient is now in complete remission. He has notbeen treated in more than six months.

[0253] Case XXV:

[0254] Dr. Falk saw this female patient (age 62) in August, 1989. Thiswoman was diagnosed with carcinoma of the pancreas. She was treated withlow doses of chemotherapy (5-FU and mitomycin) together with 300 mg ofhyaluronic acid and heat. She was having trouble with her bile ducts.She was operated on, but a tumor was not found and the bile ducts werebypassed. The patient was then treated with indomethacin and Vitamin Cin hyaluronic acid, and the heating treatments were stopped. Since hertreatment she has experienced a gain in weight and there is no evidenceof a significant tumor.

[0255] Case XXVI:

[0256] This female (age 18) patient was treated for infectiousmononucleosis. Three months of testing the patient resulted in positiveheterophile antibody tests. Patient had no energy. The patient was given50 gm of Vitamin C and 300 mg of hyaluronic acid. Within sixteen hoursof the treatment her energy increased dramatically and within two weeksthe heterophile antibody test became negative.

[0257] Case XXVII:

[0258] This woman (age 65) patient illustrates important points. Herprevious chemotherapists did not recognize they had killed most of hertumor. She had been taking chemotherapy previously. However as the tumorwas breaking up, as Dr. Falk has now concluded, there was a retention ofwater fluid in the area of the tumor (they should have looked at theultrasound for assistance). Dr. Falk saw her and treated her with heat,phloretin, Vitamin C, indomethacin and some 5-FU, all in hyaluronicacid. (According to her previous doctors, she had an enlarged tumorafter taking 5-FU. Therefore, they stopped chemotherapy). The patient isnow looking better and feeling better and there is no edema.

[0259] Case XXVIII:

[0260] This female patient had carcinoma of the ovary with intermittentto complete bowel obstruction with encasement of the bowel with tumorand also significant amounts of pleural fluid. The most striking exampleof the effect of Lasix (furosemide) occurred under the followingcircumstances. On Apr. 28 and 29, 1990, the patient excreted a totalvolume of 2,450 ml of urine over 48 hours despite the administration of0.33 per cent sodium chloride solution with added potassium chloride at40 mEq/l administered at the rate of 100-125 ml per hour. The patient'sbody weight was 40 kg. During this period of time the patient received120-200 mg of Lasix administered intravenously.

[0261] On April 30th, she received 40 mg of Lasix with added 350 mg ofhyaluronic acid administered over half of an hour. She produced adiuresis within the following 5 hours of 2,500 ml of urine. During theevening hours with no additional Lasix being given, urine output felldramatically and she excreted only 400 ml of urine from 7:00 p.m. April30th to 7:00 a.m. May 1st. At 7:30 a.m. she received 40 mg of Lasix in300 mg of hyaluronic acid administered intravenously. Over the next 8hours, this patient produced 2,600 ml of urine. This case demonstratesthe fact that even a relative insensitivity to furosemide (Lasix) can beovercome with the addition of hyaluronic acid to enhance drugpenetration to the appropriate area.

[0262] The similar type of phenomena has been observed by us in patientswhere there is a so called “hepatorenal syndrome” and where the kidneystops excreting urine due to the failure of the liver to functionadequately. Under these circumstances, urine output may decrease toessentially zero levels. This can be dramatically effected by furosemide(Lasix™) administered intravenously in hyaluronic acid, even thoughfurosemide (Lasix™) administered by itself produced no effect.

[0263] Case XXIX:

[0264] In normal healthy individuals, it was observed that addinghyaluronic acid to furosemide (Lasix™). administered at a dose of 20 mgintravenously with 300 mg of hyaluronic acid, there was an increase ofurine excretion by 3 to 5 fold as compared to that observed withfurosemide (Lasix™) alone. This is cited as evidence that hyaluronicacid increases penetration/permeation of the drug and thus facilitatesits function.

[0265] Case XXX:

[0266] This balding patient applied minoxidil (Rogaine) topically to hisscalp. There was minimal or little hair growth. Subsequently, theminoxidil was applied together with hyaluronic acid continuously every 2to 3.days. As a result this patient's hair has grown fuller and morerapidly.

[0267] Case XXXI:

[0268] This female patient (age 32) was diagnosed as having anepitheloid sarcoma on the basis of a Mayo Clinic review.

[0269] Her history of the disease dates back to Dec. 12, 1978, when shedeveloped nodularity in the left ring finger which was excised. She hashad recurrent episodes of this type of problem since then and has had anamputation of the left 4th finger. She has been extensively staged andinvestigated as she was found to have nodules of the same type ofdisease up her arm and a left axillary lymph node biopsy was positive inMarch, 1990 for an epitheloid sarcoma.

[0270] At the Mayo Clinic she received three courses of chemotherapywith mitomycin C, adriamycin, cisplatinum in high doses without anyresponse. She was scheduled for a fore-quarter amputation for thesarcoma of the left arm and forearm.

[0271] This patient was first seen by Dr. Falk on Jun. 25, 1990, and wastreated for three days with heat, phloretin-hyaluronic acid, vitaminC-hyaluronic acid, methotrexate-hyaluronic acid, and also receivedsolu-medrol. She did not have a clear response at that point in time andthe lesions remained the same.

[0272] She returned on July 23 and was treated for three consecutivedays with a reduced dose of phloretin, same dose of vitamin C-hyaluronicacid and received both naproxen and indomethacin with hyaluronic acidboth subcutaneously and intravenously. She returned home and receivedToredol™ (Syntex—non-steroidal anti-inflammatory drug) intra-muscularlyon a daily basis at a dose of 30-120 mg administered once or twice perday with 100 mg of Hyal Pharmaceutical type hyaluronic acid.

[0273] She was reassessed on August 20 and has had a dramatic decreasein size of all measurable disease by greater than 50%. In fact, at thispoint, biopsy would have to be done to ascertain if there is any viabletumor present. The treatment plan is to continue on the Toredolm andhyaluronic acid.

[0274] While the patient had some minimum response with. heat,phloretin, conventional chemotherapy with the addition of hyaluronicacid with these drugs, she did have an excellent response with thenon-steroidal anti-inflammatory drugs using all three types; Indocid™.,naproxen and Toredol™ when combined with hyaluronic acid as acarrier/penetrating vehicle to facilitate targeting to pathologicaltissue. She has had few if any of the standard side-effects that occurwith the non-steroidal anti-inflammatory drugs.

[0275] Case XXXII:

[0276] This male was diagnosed as having gastric cancer in 1988. Thetumor was in the distal third of the oesophagus at the gastro-oesopagealjunction. A Celestine tube was placed by an intraoperative abdominalprocedure and sutured to the lesser curvature of the stomach.

[0277] The patient was treated from January, 1990 up until 3 months ago(June, 1990). Repeated CAT scans have shown no change in any situation;symptomatically he had been completely well. Most recent CAT scan wasJun. 26, 1990. This raised questions in respect of some areas in theliver; however, sonographic examination suggested that these were infact homogenous.

[0278] On July 4th he had some “hot dogs” at a picnic. During the nighthe woke up with acute left upper quadrant pain which was not associatedwith nausea or vomiting. Subsequent to this he had episodes of painessentially every time he consumed any food. The pain was always thesame, felt in the back and the front of the abdomen and tended to“spread” to both flanks. It has never been associated with any directperitoneal tenderness, vomiting, diarrhea or fever and chills.Investigation included the previous CAT scan done just eight days priorto the onset of this pain, and an upper GI series with follow-through.Further CAT scan now could not be done because he was still full ofbarium.

[0279] It is important to recognize that a significant dose of Demeroljust barely relieved his pain. Further examination is unremarkable.There were no abdominal, thoracic or lymph node findings to suggest anyspread of the disease.

[0280] Dr. Falk reviewed the X-rays with a Professor at the Departmentof Radiology, Toronto General Hospital, University of Toronto. Hesuggested that the upper GI series was a classical picture of“tethering” of the small bowel. He said, this could be either fromfibrous adhesions or from neoplastic disease, or indeed, a combinationof both, as is very common with adenocarcinoma of the stomach. However,the neoplastic seedings would necessarily be very minimal, as nothingshows on the previous CAT scan.

[0281] Dr. Falk treated the patient with a combination of non-steroidalanti-inflammatories administered intravenously with hyaluronic acid inconjunction with hyperthermia and oncostatin, which is a combination ofphloretin and hyaluronic acid and achieved almost immediate relief ofpain. He can now eat without having symptoms (had lobster soup recentlyat one of the local restaurants).

[0282] Dr. Falk has also given him a supply of probanthine which hecould use, as the type of pain that occurs with these type of adhesionsis usually relieved by one of the anti-cholinergic drugs. Dr. Falk hasalso suggested to him to come back for further therapy and continue whenhe goes home on a combination of felden 10 mg b.i.d. and naprosyn 500 mgdirectly as suppository once per day and take zantac 150 mg twice a day.

[0283] In addition Dr. Falk placed him on Vibramycin (Doxycyline) 200 mgfor one day and a 100 mg daily dosage for fourteen days. This is anantibacterial agent and also blocks intracellular and anerobicglycolosis.

[0284] Follow-Up

[0285] Recent biopsies showed chronic inflammation of the lower onethird of the oesophagus (tube in oesophagus recently removed); however,there were no malignancies found.

[0286] Case XXXIII:

[0287] This man has had major tumor breakdown and this has occurred onlyafter chemotherapy was omitted from the treatment regimen. Thisinitially made him significantly more ill; this was reflected only to aminor extent in terms of his hepatic function tests. The alkalinephosphatase did become elevated. He had profound malaise, weakness,excessive fatigue and loss of appetite. This has been corrected byintensive use of indomethacin in hyaluronic acid and detoxificationprograms.

[0288] He was reassessed and was significantly better. Under ultrasound,the tumor shows virtually total necrosis. There is now increased normalliver tissue present.

[0289] Case XXXIV:

[0290] This man had a chronic abscess cavity in his pelvis with a bowelobstruction which necessitated an operation on Jan. 5, 1990. At thattime the cavity was irrigated out and drained through the perineum. Hehad an uneventful post-operative course and was discharged from hospitalon Jan. 18, 1990.

[0291] However, subsequently he developed a fever and because this hadbeen a large cavity in the pelvis, it now drained through the loweranterior part of his abdominal incision. This occurred two weeks priorto the present visit.

[0292] Dr. Falk assessed him. This is a large cavity and he thought thatthis would take 4 to 6 weeks to close. Dr. Falk instituted dailyirrigations during the 5 day working week with ampicillin, flagyl andhyaluronic acid using 500 mg of ampicillin andS500 mg of flagyl. This isa very benign form of treatment in contrast to what Dr. Falk wouldusually use which would consist of irrigation and packing the area open.

[0293] When seen later, the abscess cavity had closed over. The patientadvised that the visiting nurse on the weekends had difficulty putting acatheter into this cavity over Saturday and Sunday and in fact could notgain entrance of the catheter. Dr. Falk concluded that the cavity hadgranulated in from the “bottom up” but has done so much more rapidlythan he would have anticipated. In view of the fact that this is achronic cavity in a patient who has had a chronic and ongoing problem inthe pelvis, this is clearly an unanticipated result with a much morerapid and better resolution of a chronic abscess cavity thananticipated.

[0294] Dr. Falk has instructed the patient to call if he develops anytemperature subsequent to this. He has had a mild itching sensation overhis skin which Dr. Falk believes is probably a reaction to cold and forwhich he gave him an ointment to be applied daily.

[0295] Case XXXV:

[0296] Woman had a 9th and 12th nerve lesion, which was thought waslocated just lateral to the base of the skull. It was also thought thatshe may have had metastases in the region of the dentoid process, and anMRI scan was undertaken to try and demonstrate this. It showed somewhatabnormalities in the appropriate area. A CT scan of the region wasunhelpful.

[0297] The patient then attended The Ontario Cancer Treatment andResearch Foundation and was found to have very advanced malignantmelanoma, and was discharged from the hospital with a hopelessprognosis.

[0298] Much later the people of Ontario Cancer Treatment and ResearchFoundation were surprised and delighted to find that she had respondedunbelievably well to both positive mental imaging and to Dr. Falk'streatment. This involved hyperthermia and chemotherapy in hyaluronicacid. Dr. Falk used usual doses of Carboplastin and low doses ofMethotrexate in the hyaluronic acid.

[0299] Her chest now appears clear, and she has some persistent lesionsin kidney and liver, but these may well be under control. During thesummer, her tongue got better, and no longer deviated to the left.However, during the last three or four weeks, things have deterioratedfrom that point of view.

[0300] On recent examination, the neurological examination was entirelynormal, except for a deficit (incomplete) ingag on the left side of thepharynx, and a problem with some fasciculations and atrophy of the leftside of her tongue.

[0301] This patient has done remarkably well.

[0302] Follow-Up

[0303] More recently this woman has been administered hyaluronic acid(300 mg daily), NSAID and Vitamin C (50 gm daily). The patient appearsnow to be clear of tumour.

[0304] Case XXXVI:

[0305] This man has a mesothelioma following surgical resection and thenadjuvant treatment. It is now seven years since the initial diagnosis.In the spring of this year he developed a recurrence while in Florida.Although Dr. Falk has biopsied this three times, Dr. Falk has neverobtained cells diagnostic of malignancy. However, clinically thesituation is very clear from the CAT scan, liver function test andultrasound.

[0306] This patient has been treated with phloretin in hyaluronic acid,and heat to the area. Initially, he did not show a major response.However, on the last occasion he received no chemotherapy and onlyphloretin in hyaluronic acid with a higher dose of hyaluronic acid. Hehas had a major response and has had major problems with accumulation offluid, Dr. Falk believes, secondary to tumor breakdown. The tumorbreakdown is clearly apparent on the sonographic assessment; here thereis actual liquification of the tumor.

[0307] During his present stay, he was treated one day with hyperthermiaand received phloridzin in hyaluronic acid. However, he required anadditional two days of treatment with Vitamin C in hyaluronic acid toassist in detoxification. He also received additional diuretics Lasix™(furosemide) with hyaluronic acid.

[0308] His creatinine which was 400 m mols/l has decreased to 155ymols/l (kidney function tests—went from high to almost normal). Dr. Falkhas instructed him regarding further management. Dr. Falk does not thinkthe patient will require major further therapy as Dr. Falk thinks themajority of this tumor has been destroyed, through his own immuneresponse, the antibody and the soluble mediators being allowed to enterinto the tumor by hyaluronic acid.

[0309] In July, 1990 moderate ascites (fluid in body) occurred. Thepatient was given furosemide (Lasix™) and hyaluronic acid, indomethacinand hyaluronic acid. The patient's urine output increased substantiallyand the problem cleared.

[0310] Case XXXVII:

[0311] A 37 year old female had a carcinoma of the cervix which was aclass IIIB at the time of diagnosis. She was treated by radiation at theCross Cancer Centre, unsuccessfully, and developed further growth of thetumor which was diagnosed approximately 1 to 2 months after theradiotherapy. She was then seen by Dr. Walde at the Sault Ste.Marie-hospital. He administered epirubicin, cisplatinum at high dosesand did produce regression of the tumor as assessed by intravaginalassessment and biopsy, but apparently there was regrowth and worseningof the pain with partial ureteric obstruction demonstrated as shown by aCT scan of the abdomen and pelvis done Jun. 28, 1990.

[0312] At laparotomy, the patient had extensive tumor with major areasof necrosis but tumor extending to and involving the left common iliacartery and vein producing obstruction of the vein, the tumor wasconsidered not resectable for surgical cure because of its extent in thelateral true and false pelvis to the pelvic wall. This was assessed by aurological and two general oncological surgeons.

[0313] For this reason and because of imminent rectal obstruction, acolostomy was performed. In addition, the urological surgeon establishedan ileal conduit.

[0314] This patient was in excruciating pain continuously for severalweeks prior to and after the surgical procedure. This necessitated highdoses of intravenous morphine with only partial control of the pain. OnJuly 8th she was noted to have a major febrile reaction and a CAT scanthat day showed an abscess in the left pelvis. This was drained underCAT scan localization and the patient was placed on systemic antibioticswith only slight improvement in her infectious symptoms.

[0315] She was brought to Dr. Falk on Wednesday, July 11th. She receivedlgm of ampicillin through the draining catheter for the abscess with 500mg of hyaluronic acid. In addition, she received lmg of ampicillinintravenously and ancef and flagyl systemically in 500 mg “LifeCore™”hyaluronic acid. She also received 100 mg of indomethacin with 500 mgLifeCore™ hyaluronic acid intravenously. Within 12 hours her pain haddramatically decreased, all infective symptoms were eliminated and thedrainage from the abscess cavity had almost stopped. Her massivelyenlarged left leg due to venous and lymphatic obstruction improved toalmost normal size within a 12 hour period of time.

[0316] The patient was subsequently treated further with the sameregimen for the next 3 days resulting in total relief of pain andcontinued improvement in her status, to the point where she could bedischarged from the hospital on July 18th without anti-biotic therapy.Her systemic analgesia with morphine agents had been eliminated. Therewas no hyperthermia and no cytosis chemotherapy and/or Oncostatin(phloretin) utilized in this patient. She received anti-oxidant therapywith hyaluronic acid concomitently with the indomethacin-hyaluronicacid. This patient has demonstrated a very dramatic improvementemphasizing that the indomethacin-hyaluronic acid is targetingspecifically to pathological tissue improving macrophage function atthis site and allowing the body's immune system to perform appropriatetumor destruction.

[0317] Case Case XXXVIII:

[0318] A male patient suffering from HIV (AIDS) was treated withindomethacin (NSAID), Vitamin C, interferon and DMSO and/or hyaluronicacid and unexpectedly the patient is steadily improving.

[0319] Case XXXIX:

[0320] A male patient suffering from kyphosis suffered from constantback pain. Taking analgesics orally and rubbing back preparations ontohis back, did little to alleviate the back pain. When NSAIDS inhyaluronic acid (sodium hyaluronate) were applied directly to the back,the back pain eased and disappeared.

[0321] With indomethacin (dissolved in N-methyl glucamine) and naproxenboth dissolved in hyaluronic acid, the patient experienced side effects.However, with Toradol™ (the [+/−] form tromethamine salt of ketorolac—aprostaglandin biosynthesis inhibitor and analgesic andanti-inflammatory, the back pain eased and disappeared for some time andthere were no side effects.

[0322] Case XL:

[0323] This male patient was diagnosed with HIV (AIDS) and as a possibleresult thereof, an undetermined neoplastic disorder in the lungs. Beforetreatment, the patient was near death; white cell count was1.4×10⁹/litre. The patient was treated intravenously with indomethacin(300 mg), Vitamin C (50 gm daily) and hyaluronic acid (sodiumhyaluronate) (300 mg). After treatment, the patient's platelet countrose to 65×10⁹/litre. and his white cell count rose to 8.2×10⁹/litre.His lymphocytes doubled.

[0324] Further Tests (Animal)

[0325] Further tests were conducted on animals (rats) with the indicatedresults:

[0326] Enhanced Activity of Antibiotics with hyaluronic acid. A chronicabscess rat model was used. Sprague Dawley Rats were used. Pellets ofbacteria were inserted into each of the bellies of the rats and then therats were treated as indicated. In this model therapeutic activity ofgentamycin was compared to gentamycin in hyaluronic acid the resultsdemonstrate a statistically significant improvement by the combinationover the antibiotic alone. In this regard lower doses of antibiotic inantibiotic refractory situations were required as a result of theantibiotic being administered with hyaluronic acid. Please refer to FIG.1/1 of the drawings.

[0327] In another animal test (Grafts from ACI strain rats (black) toLewis Strain rats (white)), enhancement of graft survival was found bycombinations of immune suppressors and hyaluronic acid (HA) administeredto the Lewis Strain rats. Graft survival depends in major part on theability to suppress graft rejection with immunosuppressive agentsoptimum activity of these agents is seldom achieved as they are notdelivered to the graft site in effective concentrations; combinations ofthe agent with hyaluronic acid overcomes this difficulty. Optimizationof immunosuppressive/graft survival activity by combination of specificagents with hyaluronic acid is achieved. A standard rat skin graftrejection model was used. Cyclosporin was the immunosuppressant used.The results indicate that hyaluronic acid significantly increasedcyclosporin induced graft survival.

GRAFT SURVIVAL OF DIFFERENT TREATMENTS (JUL. 12, 1990)

[0328] CYA + HA# days CyA# days  1 20 7 20  2 19 8 20  3 19 9 20  4 2010 19  5 19 11 19  6 20 12 20 13 21 20 19 14 19 21 17 15 18 22 14 16 2023 14 17 20 24 14 18 20 25 19 19 20 mean 19.615 17.917 SE 0.213 0.723

[0329] As many changes can be made to the invention without departingfrom the scope of the invention, it is intended that all materialcontained herein be interpreted as illustrative of the invention and notin a limiting sense.

The embodiments of the invention in which an exclusive property orprivilege is claimed are as follows:
 1. A combination for administrationto a mammal which combination employs a therapeutically effective amountof a medicinal and/or therapeutic agent to treat a disease or conditionand an amount of hyaluronic acid and/or salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and subunits ofhyaluronic acid sufficient to facilitate the agent's penetration throughthe tissue (including scar tissue) at the site to be treated, throughthe cell membranes into the individual cells to be treated.
 2. Thecombination of claim 1 wherein the hyaluronic acid and/or salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand subunits of hyalurbnic acid is an amount of hyaluronic acid and/orsalts.
 3. The combination of claim 1 or 2 wherein the medicinal and/ortherapeutic agent comprises an agent selected from a free radicalscavenger, ascorbic acid, Vitamin C, an anti-cancer agent,chemotherapeutic agent, anti-viral agents, non-steroidalanti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs,anti-fungal agent, detoxifying agents, analgesic, bronchodilator,anti-bacterial agent, antibiotics, drugs for the treatment of vascularischemia anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics, immunosuppressants, lymphokynes,alpha-and-β-interferon and combinations thereof.
 4. The combination ofclaim 2 wherein the medicinal and/or therapeutic agent comprises anagent selected from ascorbic acid, an anti-cancer agent, non-steroidalanti-inflammatory drugs, antibiotics, diuretics and combinationsthereof.
 5. The combination of claim 1, 2 or 4 inclusive wherein thehyaluronic acid and/or salts thereof and or the homologues, analogues,derivatives, complexes, esters, fragments and subunits are separate fromthe medicinal and/or therapeutic agent.
 6. The combination of claim 1, 2or 4 wherein the combination is to be administered concurrently.
 7. Thecombination of claim 1, 2 or 4 wherein the combination is to beadministered at the identical site.
 8. A formulation suitable for use totreat a condition or disease, the formulation comprising atherapeutically effective amount of a medicinal and/or therapeutic agentto treat the disease or condition in an amount of hyaluronic acid and/orsalts thereof sufficient to facilitate the penetration of the agent atsite to be treated through the tissue (including scar tissue) throughcell membranes into the individual cells to be treated.
 9. Theformulation of claim 8 wherein the medicinal and/or therapeutic agentcomprises an agent selected from free radical scavenger, ascorbic acid,Vitamin C, an anti-cancer agent, chemotherapeutic agent, anti-viralagents, non-steroidal anti-inflammatory drugs (NSAID), steroidalanti-inflammatory drugs anti-fungal agent, detoxifying agents,analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs forthe treatment of vascular ischemia, anti-body monoclonal agent,minoxidil for topical application for hair growth, diuretics,immunosuppressants, lymphokynes, alpha-and-β-interferon and combinationsthereof.
 10. The formulation of claim 8 or 9 wherein the medicinaland/or therapeutic agent is selected from ascorbic acid, an anti-canceragent, non-steroidal anti-inflammatory drugs, antibiotics, diuretics andcombinations thereof.
 11. A method of treating a condition or disease ina mammal comprising administering to the mammal a therapeuticallyeffective amount of a medicinal and/or therapeutic agent to treat thedisease or condition and a sufficient amount of hyaluronic acid and/orsalts and/or homologues, analogues, derivatives, complexes, esters,fragments, and sub-units of hyaluronic acid thereof sufficient tofacilitate the penetration of the agent through the tissue (includingscar tissue) at the site to be treated through the cell membranes intothe individual cells to be treated.
 12. The method of treating acondition or disease in a mammal of claim 11, wherein the hyaluronicacid and/or salts thereof and/or homologues, analogues, derivatives,complexes, esters, fragments and subunits of hyaluronic acid is anamount of hyaluronic acid and/or salts thereof.
 13. The method of claim11 or 12 wherein the medicinal and/or therapeutic agent is selected froma free radical scavenger, ascorbic acid, Vitamin C, an anti-canceragent, chemotherapeutic agent, anti-viral agents, non-steroidalanti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugsanti-fungal agent, detoxifying agents, analgesic, bronchodilator,anti-bacterial agent, antibiotics, drugs for the treatment of vascularischemia, anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics, immunosuppressants, lymphokynes,alpha-and-β-interferon and combinations thereof.
 14. The method of claim11, 12 or 13 wherein the medicinal and/or therapeutic agent is selectedfrom ascorbic acid, an anti-cancer agent, non-steroidalanti-inflammatory drugs, antibiotics, diuretics and combinationsthereof.
 15. The method of claim 11, 12, 13 or 14 wherein thecombination is administered simultaneously at the identical site.
 16. Amethod of treating disease or condition in a mammal, comprisingadministering to the mammal a therapeutically effective amount of aformulation comprising a therapeutically effective amount of a medicinaland/or therapeutic agent to treat the disease or condition carried in anamount of hyaluronic acid and/or salts thereof sufficient to facilitatethe penetration of the agent at the site to be treated through thetissue (including scar tissue) through cell membranes into theindividual cells to be treated.
 17. The method of claim 16 wherein themedicinal and/or therapeutic agent is selected from a free radicalscavenger, ascorbic acid, Vitamin C, an anti-cancer agent,chemotherapeutic agent, anti-viral agents, non-steroidalanti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs,anti-fungal agent, detoxifying agents, analgesic, bronchodilator,anti-bacterial agent, antibiotics, drugs for the treatment of vascularischemia anti-body, monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics, immunosuppressants, lymphokynes,alpha-and-β-interferon and combinations thereof.
 18. The method of claim16 or 17 wherein the medicinal and/or therapeutic agent is selected fromascorbic acid, an anti-cancer agent, non-steroidal anti-inflammatorydrugs, antibiotics, diuretics and combinations thereof.
 19. For deliveryof a therapeutically effective amount of a medicinal and/or therapeuticagent to treat a disease or condition in a mammal, a sufficient amountof hyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the penetration of the agent at the site to betreated through the cell membranes into the individual cells to betreated.
 20. For delivery of a therapeutically effective amount of amedicinal and/or therapeutic agent to treat a disease or condition in amammal, a sufficient amount of hyaluronic acid and salts thereof tofacilitate the penetration of the agent at the site to be treatedthrough the cell membranes into the individual cells to be treated. 21.For delivery according to claim 19 or 20 wherein the medicinal and/ortherapeutic agent is selected from a free radical scavenger, ascorbicacid, Vitamin C, an anti-cancer agent, chemotherapeutic agent,anti-viral agents, non-steroidal anti-inflammatory drugs (NSAID),steroidal anti-inflammatory drugs anti-fungal agent, detoxifying agents,analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs forthe treatment of vascular ischemia, anti-body monoclonal agent,minoxidil for topical application for hair growth, diuretics,immunosuppressants, lymphokynes, alpha-and-β-interferon and combinationsthereof.
 22. For delivery according to claim 21 wherein the medicinaland/or therapeutic agent is selected from ascorbic acid, an anti-canceragent, non-steroidal anti-inflammatory drugs, antibiotics, diuretics andcombinations thereof
 23. The combination of claim 2, 3 or 4 wherein thehyaluronic acid and/or salts thereof utilized at a dose of from about 10to 1000 mg/70 kg person.
 24. The formulation of claim 8, 9 or 10inclusive wherein the hyaluronic acid and/or salts thereof is utilizedat a dose of from about 10 to 1000 mg/70 kg person.
 25. The method ofclaim 11, 12, 13, 14, 15, 16, 17 or 18 inclusive wherein the hyaluronicacid and/or salts thereof is utilized at a dose of from about 10 to 1000mg/70 kg person.
 26. The combination for the treatment of psoriasis of atherapeutically effective amount of methotrexate with hyaluronic acidand/or salts thereof sufficient to facilitate the methotrexate'spenetration through the tissue of the site to be treated.
 27. Thecombination of Hyaluronic acid and/or salts thereof with a cytotoxicchemotherapeutic agent selected from adriamycin, methotrexate, mitomycinC, bleomycin, 5-Fluorouracil, novantrone, carbo and cis platinum, andcombinations thereof.
 28. The combination of an agent selected fromphloridzin, phloretin, and 5-deoxyglucuronide of phloridzin; Vitamin C;and a non-steroidal anti-inflammatory drug, and combinations thereof tocompetitively block glucose transport in neoplastic cells and an amountof hyaluronic acid and/or salts thereof sufficient to facilitate theagent's penetration through the tissue (including scar tissue) at thesite to be treated, through the cell membranes into the individual cellsto be treated and where phloretin is the selected agent, it issolubilized by a solubilizing such as N-methyl glucamine.
 29. Thecombination of a therapeutically effective amount of a brohchodilatorwith hyaluronic acid and/or salts thereof sufficient to facilitate theagent's penetration through the tissue (including scar tissue) at thesite to be treated, through the cell membranes into the individual cellsto be treated.
 30. The combination of a therapeutically effective amountof alpha 2-interferon with hyaluronic acid and/or salts thereofsufficient to facilitate the agent's penetration through the tissue(including scar tissue) at the site to be treated, through the cellmembranes into the individual cells to be treated.
 31. The combinationof a therapeutically effective amount of a diuretic with hyaluronic acidand/or salts thereof sufficient to facilitate the agent's penetrationthrough the tissue (including scar tissue) at the site to be treated,through the cell membranes into the individual cells to be treated. 32.The combination of a therapeutically effective amount of a medicinaland/or therapeutic agent selected from an antibiotic and/oranti-bacterial agent with hyaluronic acid an/or salts thereof sufficientto facilitate the agent's penetration through the tissue (including scartissue) at the site to be treated, through the cell membranes into theindividual cells to be treated.
 33. The combination of a therapeuticallyeffective amount of ascorbic acid (Vitamin C) for the treatment ofmononucleosis with hyaluronic acid and/or salts thereof sufficient tofacilitate the agent's penetration through the tissue (including scartissue) at the site to be treated, through the cell membranes into theindividual cells to be treated.
 34. The combination of a therapeuticallyeffective amount of minoxidil for the growing of hair on a mammal withhyaluronic acid and/or salts thereof sufficient to facilitate theagent's penetration through the tissue (including scar tissue) at thesite to be treated, through the cell membranes into the individual cellsto be treated.
 35. The combination of a therapeutically effective amountof a non-steroidal anti-inflammatory drug (NSAID) with hyaluronic acidand/or salts thereof sufficient to facilitate the agent's penetrationthrough the tissue (including scar tissue) at the site to be treated,through the cell membranes into the individual cells to be treated. 36.The combination of a therapeutically effective amount of animmunosuppressant and hyaluronic acid and/or salts thereof sufficient tofacilitate the agent's penetration through the tissue (including scartissue) at the site to be treated, through the cell membranes into theindividual cells to be treated.
 37. The combination of a therapeuticallyeffective amount of an anti-viral agent and hyaluronic acid and/or saltsthereof.
 38. The combination of claim 37 where the antiviral agent is anonionic surfactant.
 39. The combination of claim 38 wherein theanti-viral agent is nonoxynol-9.
 40. A combination or formulationsuitable for use to treat a condition or disease, the formulationcomprising a therapeutically effective amount of a medicinal and/ortherapeutic agent to treat a disease or condition in an amount ofhyaluronic acid and/or salts thereof and dimethyl sulfoxide sufficientto transport the agent to the site to be treated and to penetratethrough the tissue (including scar tissue) through cell membranes intothe individual cells to be treated.
 41. The combination or formulationof claim 40 wherein the agent comprises a compound selected fromphloridzin, phloretin and 5-deoxyglucuronide of phloridzin, ascorbicacid and a non-steroidal anti-inflammatory drug.
 42. The combination orformulation of claim 2 wherein the agent comprises a compound selectedfrom phloridzin, phloretin and 5-deoxyglucuronide of phloridzin.
 43. Forthe treatment of diabetes, the combination of a therapeuticallyeffective amount of insulin and hyaluronic acid and/or salts thereofsufficient to facilitate the agent's penetration through the tissue(including scar tissue) at the site to be treated, through the cellmembranes into the individual cells to be treated.
 44. For the treatmentof post-menopausal female mammals, the combination of a therapeuticallyeffective amount of estrogen and hyaluronic acid and/or salts thereofsufficient to facilitate the agent's penetration through the tissue(including scar tissue) at the site to be treated, through the cellmembranes into the individual cells to be treated.
 45. For the controlof fertility, the combination of a therapeutically effective amount ofprogestegen and hyaluronic acid and/or salts thereof sufficient tofacilitate the agent's penetration through the tissue (including scartissue) at the site to be treated, through the cell membranes into theindividual cells to be treated.
 46. For use to treat a disease orcondition in a mammal with a medicinal and/or therapeutic agent, asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at a site in themammal to be treated by the agent passing through the tissue (includingscar tissue) through the cell membranes into the individual cells to betreated.
 47. For use to treat a disease or condition in a mammal atherapeutically effective amount of a medicinal and/or therapeutic agentwith a sufficient amount of hyaluronic acid and salts thereof tofacilitate the agent at a site in a mammal to be treated by the agentpassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 48. For the useaccording to claim 46 or 47 wherein the agent is selected from a freeradical scavenger, ascorbic acid, Vitamin C, an anti-cancer agent,chemotherapeutic agent, anti-viral agents, non-steroidalanti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs,anti-fungi agent, detoxifying agents, analgesic, bronchodilator,anti-bacterial agent, antibiotics, drugs for the treatment of vascularischemia, anti-body monoclonal agent, minoxidil -for topical applicationfor hair growth, diuretics, immunosuppressants, lymphokynes,alpha-and-β-interferon and combinations thereof.
 49. The use of claim46, 47 or 48 wherein the hyaluronic acid and/or salts thereof isutilized at a dose of from about −10 to 1000 mg/70 kg person.
 50. Thecombination of claim 1 or 2 wherein the agent is an anti-cancer agent.51. The combination of claim 1 or 2 wherein the agent is an anti-viralagent.
 52. The combination of claim 1 or 2 wherein the agent is ananti-fungal agent.
 53. The combination of claim 1 or 2 wherein the agentis an analgesic.
 54. The combination of claim 1 or 2 wherein the agentis a bronchodilator.
 55. The combination of claim 1 or 2 wherein theagent is an anti-bacterial agent.
 56. The combination of claim 1 or 2wherein the agent is an antibiotic.
 57. The combination of claim 1 or 2wherein the agent is and anti-inflammatory agent.
 58. The combination ofclaim 1 or 2 wherein the agent is an anti-body monoclonal agent.
 59. Thecombination of claim 1 or 2 wherein the agent is an immunosuppressant.60. The combination of claim 1 or 2 wherein the agent is a lymphokynes.61. The combination of claim 60 wherein the lymphokyne is interleukin-2.62. The combination of claim 1 or 2 wherein the agent is interferon. 63.The formulation of claim 8 wherein the agent is an anti-cancer agent.64. The formulation of claim 8 wherein the agent is and anti-viralagent.
 65. The formulation of claim 8 wherein the agent is an analgesic.66. The formulation of claim 8 wherein the agent is a bronchodilator.67. The formulation of claim 8 wherein the agent is an anti-bacterialagent.
 68. The formulation of claim 8 wherein the agent is anantibiotic.
 69. The formulation of claim 8 wherein the agent is ananti-inflammatory agent.
 70. The formulation of claim 8 wherein theagent is and anti-body monoclonal agent.
 71. The formulation of claim 8wherein the agent is an immunosuppressant.
 72. The formulation of claim8 wherein the agent is a lymphokyne.
 73. The formulation of claim 72wherein the lymphokyne is interleukin-2.
 74. The formulation of claim 8wherein the agent is interferon.
 75. The combination of claim 1 or 2wherein the agent is ascorbic acid (Vitamin C).
 76. The combination ofclaim 1 or 2 wherein the agent is a free radical scavenger.
 77. Thecombination of claim 1 or 2 wherein the agent is a chemotherapeuticagent.
 78. The combination of claim 1 or 2 wherein the agent is anon-ionic surfactant.
 79. The combination of claim 1 or 2 wherein theagent is a non-steroidal anti-inflammatory drugs (NSAID).
 80. Thecombination of claim 1 or 2 wherein the-agent is a steroidalanti-inflammatory drug.
 81. The combination of claim 1 or 2 wherein theagent is a detoxifying agent.
 82. The combination of claim 1 or 2wherein the agent is a drug for treating vascular ischemia.
 83. Thecombination of claim 1 or 2 wherein the agent is minoxidil for topicalapplication for hair growth.
 84. The combination of claim 1 or 2 whereinthe agent is a diuretic.
 85. The combination of claim 78 wherein thenon-ionic surfactant is nonoxynol-9.
 86. The combination of claim 78wherein the non-ionic surfactant comprises an ether or an amide linkagebetween the hydrophilic and hydrophobic portions of the molecule. 87.The combination of claim 79 wherein the non-steroidal anti-inflammatorydrug is selected from indomethacin, naproxen and the (+/−) tromethaminesalt of ketorolac and combinations thereof.
 88. The combination of claim84 wherein the diuretic is furosemide.
 89. The formulation of claim 8wherein the agent is ascorbic acid.
 90. The formulation of claim 8wherein the agent is a free radical scavenger.
 91. The formulation ofclaim 8 wherein the agent is a chemotherapeutic agent.
 92. Theformulation of claim 8 wherein the agent is a non-ionic surfactant. 93.The formulation of claim 8 wherein the agent is a non-steroidalanti-inflammatory drug (NSAID).
 94. The formulation of claim 8 whereinthe agent is a steroidal anti-inflammatory drug.
 95. The formulation ofclaim 8 wherein the agent is a detoxifying agent.
 96. The formulation ofclaim 8 wherein the agent is a drug for treating vascular ischemia. 97.The formulation of claim 8 wherein the agent is minoxidil for topicalapplication for hair growth.
 98. The formulation of claim 8 wherein theagent is a diuretic.
 99. The formulation of claim 92 wherein thenon-ionic surfactant is nonoxynol-9.
 100. The formulation of claim 92wherein the non-ionic surfactant comprises an ether or an amide linkagebetween the hydrophilic and hydrophobic portions of the molecule. 101.The formulation of claim 93 wherein the non-steroidal anti-inflammatorydrug is selected from indomethacin, naproxen and the (+/−) tromethaminesalt of ketorolac and combinations thereof.
 102. The formulation ofclaim 98 wherein the diuretic is furbsemide.
 103. A combination suitablefor use to treat a person with AIDS, the combination comprisingtherapeutically effective amounts of ascorbic acid (Vitamin C),non-steroidal anti-inflammatory drugs, and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at a site to be treated through the tissue(including scar tissue) through cell membranes into the individual cellsto be treated.
 104. The combination of claim 103 wherein the amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 105. The combination ofclaim 103 or 104 further comprising interferon.
 106. The combination ofclaim 103 or 104 wherein the non-steroidal anti-inflammatory drug isindomethacin.
 107. The combination of claim 103, 104, 105 or 106 whereinthe amount of hyaluronic acid and salts thereof or other forms thereofmay be substituted by dimethyl sulfoxide (either in whole or in part).108. A combination suitable for use to treat a person with cancer, thecombination comprising therapeutically effective amounts of ascorbicacid (Vitamin C), non-steroidal anti-inflammatory drugs, and asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at a site to betreated through the tissue (including scar tissue) through cellmembranes into the individual cells to be treated.
 109. The combinationof claim 108 wherein the amount of hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 110. The combination of claim 108 or 109 wherein thenon-steroidal anti-inflammatory drug is selected from indomethacin,naproxen and the (+/−) tromethamine salt of ketorolac.
 111. For thetreatment of cancer, the administration of a therapeutically effectiveamount of ascorbic acid, a non-steroidal anti-inflammatory drug, and atleast one of an agent selected from an anti-cancer drug chemotherapeuticagent and detoxifying drug, and a sufficient amount of hyaluronic acidand salts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 112. For the use of claim 111 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 113. For the use of claim111 or 112 wherein the non-steroidal anti-inflammatory drug is selectedfrom indomethacin, naproxen and ketorolac trimethamine.
 114. For hairgrowth, the topical administration of a therapeutically effective amountof minoxidil and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 115. For use to treat herpes, canker sores andshingles, the administration of a therapeutically effective amount ofnonionic surfactant and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 116. For the use of claim 115 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 117. For the use of claim115 or 116 wherein the nonionic surfactant comprises an ether or anamide linkage between the hydrophilic and hydrophobic portions of themolecule.
 118. For the use in claim 115 or 116, the nonionic surfactantis nonoxynol-9.
 119. For use to treat renal failure, cardiacinsufficiency, hypertension and edema, the administration of aneffective amount of a diuretic and a sufficient amount of hyaluronicacid and salts thereof and/or homologues, analogues, derivatives,complexes, esters, fragments and sub-units of hyaluronic acid tofacilitate the agent at the site to be treated by the agents passingthrough the tissue (including scar tissue) through the cell membranesinto the individual cells to be treated.
 120. For the use of claim 119wherein the hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid is hyaluronic acid and/or salts thereof.
 121. For theuse of claim 119 and 120 wherein the diuretic is furosemide.
 122. Foruse to treat infection, the administration of a therapeuticallyeffective amount of an agent selected from antibiotics, antibacterials,antimicrobials and combinations therof with or without ascorbic acid anda sufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 123.For the use of claim 122 wherein the hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 124. For use to treat acne, the administration of atherapeutically effective amount of an agent selected from antibiotics,antibacterials, antimicrobicals and combinations therof with or withoutascorbic acid and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 125. For the use of claim 124 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 126. For use in thetransplant of organs and tissue to reduce the likelihood of therejection thereof, the administration of a therapeutically effectiveamount of an immunosuppressant and a sufficient amount of hyaluronicacid and salts thereof and/or homologues, analogues, derivatives,complexes, esters, fragments and sub-units of hyaluronic acid tofacilitate the agent at the site to be treated by the agents passingthrough the tissue (including scar tissue) through the cell membranesinto the individual cells to be treated.
 127. For the use in claim 126wherein the hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid is hyaluronic acid and/or salts thereof.
 128. For theuse in claim 126 or 127 wherein the immunosuppressant is a cyclosporin.129. For use in treating inflammation, the administration of atherapeutically effective amount of a non-steroidal anti-inflammatoryagent (NSAID) and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 130. For the use in claim 129 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 131. For use in assistingin the elimination of tumour break down material (including toxins,residue and debris) in a person suffering from tumours, theadministration of a therapeutically effective amount of a non-steroidalanti-inflammatory agent (NSAID) and a sufficient amount of hyaluronicacid and salts thereof and/or homologues, analogues, derivatives,complexes, esters, fragments and sub-units of hyaluronic acid tofacilitate the agent at the site to be treated by the agents passingthrough the tissue (including scar tissue) through the cell membranesinto the individual cells to be treated.
 132. For the use in claim 131wherein the hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid is hyaluronic acid and/or salts thereof.
 133. For theuse of claim 129, 130, 131 or 132 wherein the non-steroidalanti-inflammatory agent (NSAID) is selected from indomethacin, naproxenand [±] tromethamine salt of Ketorolac.
 134. For use in detoxifying apatient of toxins, the administration of a therapeutically amount of adetoxifying agent and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes,. esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 135. For the use of claim 134 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 136. For the use of claim134 or 135 in the form of peritoneal dialysis.
 137. For use to treat apatient. suffering from respiratory difficulties, the administration ofa therapeutically effective amount of a bonchodilator or the like and asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 138.For the use of claim 137 wherein the hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 139. For use to treat vascular ischemia, the administration ofa therapeutically effective amount ot an agent suitable for use to treatthe condition and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 140. For the use of claim 139 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 141. For use to treat aperson suffering from AIDS (HIV virus) the administration oftherapeutically effective amounts of, ascorbic acid (Vitamin C), anon-steroidal anti-inflammatory agent and an agent selected frominterferon, an anti-viral agent, an antibiotic, dimethyl sulfoxide[DMSO] and combinations thereof; a sufficient amount of hyaluronic acidand salts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 142. For the use of claim 141 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 143. For the use of claim141 or 142 wherein Dimethyl Sulfoxide (DMSO) is substituted for some orall of the forms of hyaluronic acid.
 144. For the use of claim 141, 142or 143 wherein the non-steriodal anti-inflammatory drug is selected fromindomethacin, naproxen and [±] tromethamine salt of Ketorolac.
 145. Foruse to treat herpes, the administration of a therapeutically effectiveamount of non-ionic surfactant and a sufficient amount of hyaluronicacid and salts thereof and/or homologues, analogues, derivatives,complexes, esters, fragments and sub-units of hyaluronic acid tofacilitate the agent at the site to be treated by the agents passingthrough the tissue (including scar tissue) through the cell membranesinto the individual cells to be treated.
 146. For use to treat cankersores, the administration of a therapeutically effective amount ofnon-ionic surfactant and a sufficient amount of hyaluronic acid andsalts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 147. For use to treat herpes zoster (shingles), theadministration of a therapeutically effective amount of non-ionicsurfactant and a sufficient amount of hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid to facilitate the agent at the site tobe treated by the agents passing through the tissue (including scartissue) through the cell membranes into the individual cells to betreated.
 148. For the use of claim 145, 146 or 147 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 149. For the use of claim145, 146, 147 or 148, wherein the non-ionic sufactant comprises an etheror an amide linkage between the hydrophilic and hydropholic portions ofthe molecule.
 150. For the use of claim 149 wherein the non-ionicsurfactant comprises nonoxynol-9.
 151. For use to treat infectionssurrounding implants in a patient, the administration of atherapeutically effective amount of an antibiotic for the infectedtissue surrounding the implant and a sufficient amount of hyaluronicacid and salts thereof and/or homologues, analogues, derivatives,complexes, esters, fragments and sub-units of hyaluronic acid tofacilitate the, agent at the site to be treated by the agents passingthrough the tissue (including scar tissue) through the cell membranesinto the individual cells to be treated.
 152. For use to treat a patientsuffering from brain tumours and in respect of which swelling hasoccurred, the administration of a therapeutically effective amount ofdimethyl sulfoxide and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 153. The use of claim 151 or 152 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 154. For the treatment ofmononucleosis, the administration of a therapeutically effective amountof ascorbic acid (Vitamin C) and a sufficient amount of hyaluronic acidand salts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 155. For the treatment of herpes simplex type I andII, the administration of a therapeutically effective amount of anon-ionic surfactant and a sufficient amount of hyaluronic acid andsalts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 156. For the use of claim 155 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 157. For the use of claim155 or 156 wherein the non-ionic surfactant comprises an ether or anamide linkage between the hydrophilic and hydropholic protions of themolecure.
 158. For the use of claim 157 wherein the non-ionic surfactantis nonoxynol-9.
 159. For the use to treat herpes, herpes simplex type Iand II and herpes zoster (shingles), the administration of atherapeutically effective amount of a surfactant selected from ananionic surfactant and a cationic surfactant and combinations thereofand a sufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 160.For the use of claim 159 wherein the hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 161. For the use of claim 159 or 160 wherein the anionicsurfactant comprises cetyl pyridinium chloride and the like and thecationic surfactant comprises benzalkonium chloride and the like. 162.For the treatment of a patient suffering from cancer, the administrationof a therapeutically effective amount of a non-steroidalanti-inflammatory agent a therapeutically effective amount of ananti-cancer agent, and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 163. For the use of claim 162 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 164. For the use of claim162 or 163 further comprising a therapeutically effective amount ofAscorbic Acid (Vitamin C).
 165. For the use of claim 162, 163 or 164wherein the non-steroidal anti-inflammatory agent is selected fromindomethacin, naproxen and [±] tromethamine salt of Ketorolac.
 166. Foruse to treat canker sores, the administration of, a therapeuticallyeffective amount of (alpha) 2-interferon with an amount of hyaluronicacid and salts thereof and/or homologues, analogues, derivatives,complexes, esters, fragments and sub-units of hyaluronic acid sufficientto facilitate the agent at the site to be treated by the agents passingthrough the tissue (including scar tissue) through the cell membranesinto the individual cells to be treated.
 167. For the use of claim 166wherein the hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid is hyaluronic acid and/or salts thereof.
 168. For use totreat pain, the administration of a therapeutically effective amount ofa non-steroidal anti-inflammatory agent and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 169. For the use ofclaim 168 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.170. For the use of claim 168 or 169 wherein the non-steriodalanti-inflammatory comprises indomethacin, naproxen and a combinationthereof.
 171. For the use of claim 168 or 169 wherein the non-steroidalanti-inflammatory comprises [±] tromethamine salt of Ketorolac.
 172. Foruse to treat a patient suffering from HIV (AIDS), the administration ofa therapeutically effective amount of Ascorbic Acid (Vitamin C), atherapeutically effective amount of a non-steroidal anti-inflammatoryand a sufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 173.For the use of claim 172 wherein the hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 174. For the use of claim 172 or 173 wherein the non-steroidalanti-inflammatory is indomethacin.
 175. For the use of claim 154 whereinthe hyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 176. For the treatment ofcancer, the combination of a therapeutically effective amount ofascorbic acid, a non-steroidal anti-inflammatory drug, and at least oneof an agent selected from an anti-cancer drug, chemotherapeutic agentand detoxifying drug, and a sufficient amount of hyaluronic acid andsalts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 177. The combination of claim 176 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 178. The combination ofclaim 176 or 177 wherein the non-steroidal anti-inflammatory drug isselected from indomethacin, naproxen and ketorolac tromethamine. 179.For hair growth, the combination of a therapeutically effective amountof minoxidil, and at least one of an agent selected from an anti-cancerdrug chemotherapeutic agent and detoxifying drug, and a sufficientamount of hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid to facilitate the agent at the site to be treated by theagents passing through the tissue (including scar tissue) through thecell membranes into the individual cells to be treated.
 180. For use totreat herpes, canker sores and shingles, the combination of atherapeutically effective amount of nonionic surfactant and a sufficientamount of hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid to facilitate the agent at the site to be treated by theagents passing through the tissue (including scar tissue) through thecell membranes into the individual cells to be treated.
 181. Thecombination of claim 180 wherein the hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 182. The combination of claim 180 or 181 wherein the nonionicsurfactant comprises an ether or an amide linkage between thehydrophilic and hydrophobic portions of the molecule.
 183. For the usein claim 180 or 181, the nonionic surfactant is nonoxynol-9.
 184. Foruse to treat renal failure, cardiac insufficiency, hypertension andedema, the combination of an effective amount of a diuretic and asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 185.The combination of claim 184 wherein the hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid is hyaluronic acid and/orsalts thereof.
 186. The combination of claim 184 and 185 wherein thediuretic is furosemide.
 187. For use to treat infection, the combinationof a therapeutically effective amount of an agent selected fromantibiotics, antibacterials, antimicrobials and combinations therof withor without ascorbic acid and a sufficient amount of hyaluronic acid andsalts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 184. The combination of claim 187 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 189. For use to treatacne, the combination of a therapeutically effective amount of an agentselected from antibiotics, antibacterials, antimicrobicals andcombinations therof with or without ascorbic acid and a sufficientamount of hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid to facilitate the agent at the site to be treated by theagents passing through the tissue (including scar tissue) through thecell membranes into the individual cells to be treated.
 190. Thecombination of claim 189 wherein the hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 191. For use in the transplant of organs and tissue to reducethe likelihood of the rejection thereof, the combination of antherapeutically effective amount of an immunosuppressant and asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 192.The combination of claim 191 wherein the hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid is hyaluronic acid and/orsalts thereof.
 193. The combination of claim 190 or 191 wherein theimmunosuppressant is a cyclosporin.
 194. For use in treatinginflammation, the combination of a therapeutically effective amount of anon-steroidal anti-inflammatory agent (NSAID) and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 195. The combinationclaim 194 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.196. For use in assisting in the elimination of tumour break downmaterial (including toxins, residue and debris) in a person sufferingfrom tumours, the combination of a therapeutically effective amount of anon-steroidal anti-inflammatory agent (NSAID) and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 197. The combinationof claim 132 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.198. The combination of claim 194, 195, 196 or 197 wherein thenon-steroidal anti-inflammatory agent (NSAID) is selected fromindomethacin, naproxen and:[±] tromethamine salt of Ketorolac.
 199. Foruse in detoxifying a patient of toxins, the combination of atherapeutically amount of a detoxifying agent and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 200. The combinationof claim 199 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.201. The combination of claim 199 or 200 in the form of peritonealdialysis.
 202. For use to treat a patient suffering from respiratorydifficulties, the combination of a therapeutically effective amount of abonchodilator or the like and a sufficient amount of hyaluronic acid andsalts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 203. The combination of claim 202 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 204. For use to treatvascular ischemia, the combination of a therapeutically effective amountof an agent suitable for use to treat the condition and a sufficientamount of hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid to facilitate the agent at the site to be treated by theagents passing through the tissue (including scar tissue) through thecell membranes into the individual cells to be treated.
 205. Thecombination claim 204 wherein the hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 206. For use to treat a person suffering from AIDS (HIV virus),the combination of therapeutically effective amounts of, ascorbic acid(Vitamin C), a non-steroidal anti-inflammatory agent and an agentselected from interferon, an anti-viral agent, an antibiotic, dimethylsulfoxide [DMSO] and combinations and thereof a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 207. The combinationof claim 206 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.208. The combination of claim 206 or 207 wherein Dimethyl Sulfoxide(DMSO) is substituted for some or all of the forms of hyaluronic acid.209. The combination of claim 206, 207 or 208 wherein the non-steriodalanti-inflammatory drug is selected from indomethacin, naproxen and [±]tromethamine salt of Ketorolac.
 210. For use to treat herpes, thecombination of a therapeutically effective amount of non-ionicsurfactant and a sufficient amount of hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid to facilitate the agent at the site tobe treated by the agents passing through the tissue (including scartissue) through the cell membranes into the individual cells to betreated.
 211. For use to treat canker sores, the combination of atherapeutically effective amount of non-ionic surfactant and asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 212.For use to treat herpes zoster (shingles), the combination of atherapeutically effective amount of non-ionic surfactant and asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 213.The combination of claim 210, 211 or 212 wherein the hyaluronic acid andsalts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid is hyaluronic acidand/or salts thereof.
 214. The combination of claim 210, 211, 212 or213, wherein the non-ionic sufactant comprises an ether or an amidelinkage between the hydrophilic and hydropholic portions of themolecule.
 215. The combination of claim 214 wherein the non-ionicsurfactant comprises nonoynol-9.
 216. For use to treat infectionssurrounding implants in a patient, the combination of a therapeuticallyeffective amount of an antibiotic for the infected tissue surroundingthe implant and a sufficient amount of hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid to facilitate the agent at the site tobe treated by the agents passing through the tissue (including scartissue) through the cell membranes into the individual cells to betreated.
 217. For use to test a patient suffering from brain tumours andin respect of which swelling has occurred, the administration of atherapeutically effective amount of dimethyl sulfoxide and a sufficientamount of hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid to facilitate the agent at the site to be treated by theagents passing through the tissue (including scar tissue) through thecell membranes into the individual cells to be treated.
 218. Thecombination of claim 216 or 217 wherein the hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid is hyaluronic acid and/orsalts thereof.
 219. For the treatment of mononucleosis, the combinationof a therapeutically effective amount of ascorbic acid (Vitamin C) and asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 220.For the treatment of herpes simplex type I and II, the combination of atherapeutically effective amount of a non-ionic surfactant and asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 221.The combination of claim 220 wherein the hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid is hyaluronic acid and/orsalts thereof.
 222. The combination of claim 220 or 221 wherein thenon-ionic surfactant comprises an ether or an amide linkage between thehydrophilic and hydropholic protions of the molecure.
 223. For the useof claim 222 wherein the non-ionic surfactant is nonoxynol-9.
 224. Forthe use to treat herpes, herpes simplex type I and II and herpes zoster(shingles), the administration of a therapeutically effective amount ofa surfactant selected from an anionic surfactant and a cationicsurfactant and combinations thereof and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 225. The combinationof claim 224 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.226. The combination of claim 223 or 224 wherein the anionic surfactantcomprises cetyl pyridinium chloride and the like and the cationicsurfactant comprises benzalkonium chloride and the like.
 227. For theuse of claim 219 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.228. For the treatment of a patient suffering from cancer, thecombination of a therapeutically effective amount of a non-steroidalanti-inflammatory agent a therapeutically effective amount of ananti-cancer agent, and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 229. The combination of claim 228 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 230. The combination ofclaim 228 or 229 further comprising a therapeutically effective amountof Ascorbic Acid (Vitamin C).
 231. The combination of claim 228, 229 or230 wherein the non-steroidal anti-inflammatory agent is selected fromindomethacin, naproxen and [±] tromethamine salt of Ketorolac.
 232. Foruse to treat canker sores, the combination of a therapeuticallyeffective amount of alpha 2-interferon with a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid sufficient to facilitate the agent at the site to be treated by theagents passing through the tissue (including scar tissue) through thecell membranes into the individual cells to be treated.
 233. Thecombination of claim 232 wherein the hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 234. For use to treat back pain, the combination of atherapeutically effective amount of a non-steroidal anti-inflammatoryagent and a sufficient amount of hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid to facilitate the agent at the site tobe treated by the agents passing through the tissue (including scartissue) through the cell membranes into the individual cells to betreated.
 235. The combination of claim 234 wherein the hyaluronic acidand salts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid is hyaluronic acidand/or salts thereof.
 236. The combination of claim 234 or 235 whereinthe non-steroidal anti-inflammatory comprises indomethacin, naproxen anda combination thereof.
 237. The combination of claim 234 or 235 whereinthe non-steroidal anti-inflammatory comprises [±] tromethamine salt ofKetorolac.
 238. For use to treat a patient suffering from HIV (AIDS),the combination of a therapeutically effective amount of Ascorbic Acid(Vitamin C), a therapeutically effective amount of a non-steroidalanti-inflammatory and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 239. The combination of claim 238 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 240. The combination ofclaim 237 or 239 wherein the non-steroidal anti-inflammatory isindomethacin.
 241. The combination of claim 238, 239 or 240 furthercomprising interferon.
 242. The combination of claim 238, 239, 240 or241 further comprising Dimethyl Sulfoxide (DMSO) and wherein some or allof the forms of the hyaluronic acid may be substituted bytherapeutically effective amount of dimethyl sulfoxide.
 243. For the useof claim 174, 175 or 176 further comprising interferon.
 244. For the usethe claim 174, 175, 176 or 243 further comprising dimethyl sulfoxide andwherein some or all of the forms of the hyaluronic acid may besubstituted by therapeutically effective amounts of dimethyl sulfoxide.245. For enhanced neoplastic activity and effect, the administration ofa therapeutically effective amount of ascorbic acid and a sufficientamount of hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid to facilitate the agent at the site to be treated by theagents passing through the tissue (including scar tissue) through thecell membranes into the individual cells to be treated.
 246. The use ofclaim 245 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.247. For enhanced neoplastic activity and effect, the combination of atherapeutically effective amount of ascorbic acid and a sufficientamount of hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid to facilitate the agent at the site to be treated by theagents passing through the tissue (including scar tissue) through thecell membranes into the individual cells to be treated.
 248. Thecombination of claim 247 wherein the hyaluronic acid and salts thereofand/or homologues, analogues, derivatives, complexes, esters, fragmentsand sub-units of hyaluronic acid is hyaluronic acid and/or saltsthereof.
 249. A method of increasing activity of macrophages in mammalssuffering from disease, the administration of an effective amount of anon-steroidal anti-inflammatory agent (NSAID) and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated sufficient to increaseactivity of macrophages in mammal suffering disease.
 250. The use ofclaim 249 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.251. The use of claim 249 or 250 wherein the non-steroidalanti-inflammatory agent (NSAID) is selected from indomethacin, naproxen,and [±] tromethamine salt of Ketorolac.
 252. For increasing activity ofmacrophages in mammals suffering from disease, the combination of aneffective amount of a non-steroidal anti-inflammatory agent (NSAID) anda sufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treatedsufficient to increase activity of macrophages in mammal sufferingdisease.
 253. The combination of claim 252 wherein the hyaluronic acidand salts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid is hyaluronic acidand/or salts thereof.
 254. The combination of claim 252 or 253 whereinthe non-steroidal anti-inflammatory agent (NSAID) is selected fromindomethacin, naproxen, and [±] tromethamine salt of Ketorolac.
 255. Amethod of decreasing the side effects of administering a non-steroidalanti-inflammatory agent (NSAID) in a patient suffering a disease takingnon-steroidal anti-inflammatory agent (NSAID), the administration of aneffective amount of a non-steroidal anti-inflammatory agent (NSAID) fortreating the patient and a sufficient amount of hyaluronic acid andsalts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated to decrease the side effects of the non-steroidalanti-inflammatory.
 256. The use of claim 255 wherein the non-steroidalanti-inflammatory is indomethacin.
 257. The use of claim 255 wherein thenon-steroidal anti-inflammatory agent (NSAID) is selected fromindomethacin, naproxen, and [±] tromethamine salt of Ketorolac.
 258. Fordecreasing the side effects of administering a non-steroidalanti-inflammatory agent, the combination of an effective amount of anon-steroidal anti-inflammatory agent (NSAID) for treating the patientand a sufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated todecrease the side effects of the non-steroidal anti-inflammatory. 259.The combination of claim 258 wherein the non-steroidal anti-inflammatoryis indomethacin.
 260. The combination of claim 258 wherein thenon-steroidal anti-inflammatory agent (NSAID) is selected fromindomethacin, naproxen, and [±] tromethamine salt of Ketorolac.
 261. Forthe prevention of topical infection, the administration of an effectiveamount of an anti-metabolite and a sufficient amount of hyaluronic acidand salts thereof and/or homologues, analogues, derivatives, complexes,esters, fragments and sub-units of hyaluronic acid to facilitate theagent at the site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 262. For the use of claim 261 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 263. For the prevention oftopical infection, the combination of an effective amount of ananti-metabolite and a sufficient amount of hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid to facilitate the agent atthe site to be treated by the agents passing through the tissue(including scar tissue) through the cell membranes into the individualcells to be treated.
 264. The combination of claim 263 wherein thehyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid is hyaluronic acid and/or salts thereof.
 265. For use to treat bonepain, muscle pain and/or inflammation, the administration of aneffective amount of Ascorbic Acid (vitamin C) and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 266. The-use of claim265 wherein the hyaluronic acid and salts thereof and/or homologues,analogues, derivatives, complexes, esters, fragments and sub-units ofhyaluronic acid is hyaluronic acid and/or salts thereof.
 267. For use totreat bone pain, muscle pain and/or inflammation, the combination ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 268. The combinationof claim 267 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.269. For enhancing prostaglandin synthesis inhibition, the combinationof a therapeutically effective amount of aceytylsalicylic acid and asufficient amount of hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid to facilitate the agent at the site to betreated by the agents passing through the tissue (including scar tissue)through the cell membranes into the individual cells to be treated. 270.The combination of claim 269 wherein the hyaluronic acid and saltsthereof and/or homologues, analogues, derivatives, complexes, esters,fragments and sub-units of hyaluronic acid is hyaluronic acid and/orsalts thereof.
 271. For the use to enhance prostaglandin synthesisinhibition in a patient, the administration of a therapeuticallyeffective amount of aceytylsalicylic acid and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 272. For the use ofclaim 271 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.273. For enhancing oxygenation of tissue by perfusion fluid bathing thetissue, the combination of perfusate fluid and a sufficient amount ofhyaluronic acid and salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments and sub-units of hyaluronicacid to facilitate the agent at the site to be treated by the agentspassing through the tissue (including scar tissue) through the cellmembranes into the individual cells to be treated.
 274. The combinationof claim 273 wherein the hyaluronic acid and salts thereof and/orhomologues, analogues, derivatives, complexes, esters, fragments andsub-units of hyaluronic acid is hyaluronic acid and/or salts thereof.